| 2010-04-05 | @ CHA | 1 | L 0-6 | 0-1 | 3 | 38,935 | Jake Westbrook | Mark Buehrle | Mark Buehrle | Jake Westbrook | | 0 | 6 | -6 |
| 2010-04-07 | @ CHA | 2 | W 5-3 | 1-1 | 3 | 19,514 | Fausto Carmona | Jake Peavy | Fausto Carmona | Randy Williams | Chris Perez | 5 | 9 | -4 |
| 2010-04-08 | @ CHA | 3 | W 5-3 | 2-1 | 2 | 18,637 | Justin Masterson | Gavin Floyd | Jensen Lewis | J.J. Putz | Chris Perez | 10 | 12 | -2 |
| 2010-04-09 | @ DET | 4 | L 2-5 | 2-2 | 3 | 45,010 | David Huff | Rick Porcello | Rick Porcello | David Huff | Jose Valverde | 12 | 17 | -5 |
| 2010-04-10 | @ DET | 5 | L 2-4 | 2-3 | 3 | 35,332 | Mitch Talbot | Jeremy Bonderman | Jeremy Bonderman | Mitch Talbot | Ryan Perry | 14 | 21 | -7 |
| 2010-04-11 | @ DET | 6 | L 8-9 | 2-4 | 4 | 26,081 | Jake Westbrook | Justin Verlander | Phil Coke | Chris Perez | | 22 | 30 | -8 |
| 2010-04-12 | vs TEX | 7 | L 2-4 | 2-5 | 4 | 42,061 | Fausto Carmona | Rich Harden | Frank Francisco | Jamey Wright | Neftali Feliz | 24 | 34 | -10 |
| 2010-04-14 | vs TEX | 8 | L 2-6 | 2-6 | 5 | 10,071 | Justin Masterson | Colby Lewis | Colby Lewis | Justin Masterson | Neftali Feliz | 26 | 40 | -14 |
| 2010-04-15 | vs TEX | 9 | W 3-2 | 3-6 | 4 | 10,198 | David Huff | Matt Harrison | David Huff | Matt Harrison | | 29 | 42 | -13 |
| 2010-04-16 | vs CHA | 10 | W 6-2 | 4-6 | 3 | 10,421 | Mitch Talbot | Mark Buehrle | Mitch Talbot | Mark Buehrle | | 35 | 44 | -9 |
| 2010-04-17 | vs CHA | 11 | W 3-2 | 5-6 | 3 | 12,885 | Jake Westbrook | Jake Peavy | Jensen Lewis | Matt Thornton | Chris Perez | 38 | 46 | -8 |
| 2010-04-18 | vs CHA | 12 | W 7-4 | 6-6 | 3 | 10,564 | Fausto Carmona | Gavin Floyd | Fausto Carmona | Gavin Floyd | Chris Perez | 45 | 50 | -5 |
| 2010-04-20 | @ MIN | 13 | L 1-5 | 6-7 | 3 | 38,985 | Justin Masterson | Kevin Slowey | Kevin Slowey | Justin Masterson | | 46 | 55 | -9 |
| 2010-04-21 | @ MIN | 14 | L 0-6 | 6-8 | 3 | 39,044 | David Huff | Francisco Liriano | Francisco Liriano | David Huff | | 46 | 61 | -15 |
| 2010-04-22 | @ MIN | 15 | W 8-1 | 7-8 | 3 | 38,810 | Mitch Talbot | Scott Baker | Mitch Talbot | Scott Baker | | 54 | 62 | -8 |
| 2010-04-23 | @ OAK | 16 | L 0-10 | 7-9 | 3 | 11,547 | Jake Westbrook | Justin Duchscherer | Justin Duchscherer | Jake Westbrook | | 54 | 72 | -18 |
| 2010-04-24 | @ OAK | 17 | W 6-1 | 8-9 | 3 | 15,873 | Fausto Carmona | Brett Anderson | Fausto Carmona | Chad Gaudin | | 60 | 73 | -13 |
| 2010-04-25 | @ OAK | 18 | L 0-11 | 8-10 | 4 | 16,946 | Justin Masterson | Gio Gonzalez | Gio Gonzalez | Justin Masterson | | 60 | 84 | -24 |
| 2010-04-26 | @ ANA | 19 | L 2-5 | 8-11 | 4 | 34,837 | David Huff | Jered Weaver | Jered Weaver | David Huff | Brian Fuentes | 62 | 89 | -27 |
| 2010-04-27 | @ ANA | 20 | W 9-2 | 9-11 | 4 | 39,619 | Mitch Talbot | Joe Saunders | Mitch Talbot | Joe Saunders | | 71 | 91 | -20 |
| 2010-04-28 | @ ANA | 21 | L 3-4 | 9-12 | 4 | 34,190 | Jake Westbrook | Ervin Santana | Brian Fuentes | Joe Smith | | 74 | 95 | -21 |
| 2010-04-30 | vs MIN | 22 | L 3-9 | 9-13 | 4 | 14,124 | Fausto Carmona | Kevin Slowey | Kevin Slowey | Fausto Carmona | | 77 | 104 | -27 |
| 2010-05-01 | vs MIN | 23 | W 5-4 | 10-13 | 4 | 13,832 | Justin Masterson | Jeff Manship | Jamey Wright | Alex Burnett | | 82 | 108 | -26 |
| 2010-05-02 | vs MIN | 24 | L 3-8 | 10-14 | 4 | 12,619 | David Huff | Francisco Liriano | Francisco Liriano | David Huff | | 85 | 116 | -31 |
| 2010-05-03 | vs TOR | 25 | L 1-5 | 10-15 | 4 | 10,117 | Mitch Talbot | Brett Cecil | Brett Cecil | Mitch Talbot | | 86 | 121 | -35 |
| 2010-05-04 | vs TOR | 26 | L 5-8 | 10-16 | 4 | 10,387 | Jake Westbrook | Ricky Romero | Ricky Romero | Jensen Lewis | Kevin Gregg | 91 | 129 | -38 |
| 2010-05-05 | vs TOR | 27 | L 4-5 | 10-17 | 4 | 12,563 | Fausto Carmona | Brandon Morrow | Jason Frasor | Chris Perez | | 95 | 134 | -39 |
| 2010-05-08 | vs DET | 28 | L 4-6 | 10-18 | 5 | 18,428 | Justin Masterson | Justin Verlander | Justin Verlander | Kerry Wood | Jose Valverde | 99 | 140 | -41 |
| 2010-05-09 | vs DET | 29 | W 7-4 | 11-18 | 4 | 16,980 | Mitch Talbot | Max Scherzer | Mitch Talbot | Max Scherzer | Chris Perez | 106 | 144 | -38 |
| 2010-05-11 | @ KCA | 30 | W 8-2 | 12-18 | 4 | 15,930 | Jake Westbrook | Brian Bannister | Jake Westbrook | Brian Bannister | | 114 | 146 | -32 |
| 2010-05-12 | @ KCA | 31 | W 4-0 | 13-18 | 5 | 11,803 | Fausto Carmona | Kyle Davies | Fausto Carmona | Kyle Davies | | 118 | 146 | -28 |
| 2010-05-13 | @ KCA | 32 | L 4-6 | 13-19 | 4 | 28,361 | David Huff | Zack Greinke | Zack Greinke | David Huff | Joakim Soria | 122 | 152 | -30 |
| 2010-05-14 | @ BAL | 33 | L 1-8 | 13-20 | 4 | 25,902 | Justin Masterson | Jeremy Guthrie | Jeremy Guthrie | Justin Masterson | | 123 | 160 | -37 |
| 2010-05-15 | @ BAL | 34 | W 8-2 | 14-20 | 4 | 29,545 | Mitch Talbot | Brian Matusz | Mitch Talbot | Alfredo Simon | | 131 | 162 | -31 |
| 2010-05-16 | @ BAL | 35 | W 5-1 | 15-20 | 4 | 29,323 | Jake Westbrook | Mark Hendrickson | Jake Westbrook | Mark Hendrickson | | 136 | 163 | -27 |
| 2010-05-17 | @ TBA | 36 | L 3-4 | 15-21 | 4 | 18,879 | Fausto Carmona | Jeff Niemann | Andy Sonnanstine | Jamey Wright | | 139 | 167 | -28 |
| 2010-05-18 | @ TBA | 37 | L 2-6 | 15-22 | 4 | 17,093 | David Huff | David Price | David Price | David Huff | | 141 | 173 | -32 |
| 2010-05-19 | vs KCA | 38 | L 4-8 | 15-23 | 4 | 10,916 | Justin Masterson | Gil Meche | Bruce Chen | Kerry Wood | | 145 | 181 | -36 |
| 2010-05-20 | vs KCA | 39 | L 3-9 | 15-24 | 4 | 13,953 | Mitch Talbot | Luke Hochevar | Luke Hochevar | Mitch Talbot | | 148 | 190 | -42 |
| 2010-05-21 | vs CIN | 40 | L 4-7 | 15-25 | 5 | 23,028 | Jake Westbrook | Bronson Arroyo | Bronson Arroyo | Aaron Laffey | Francisco Cordero | 152 | 197 | -45 |
| 2010-05-22 | vs CIN | 41 | L 4-6 | 15-26 | 5 | 25,531 | Fausto Carmona | Johnny Cueto | Johnny Cueto | Fausto Carmona | | 156 | 203 | -47 |
| 2010-05-23 | vs CIN | 42 | W 4-3 | 16-26 | 5 | 21,044 | David Huff | Homer Bailey | David Huff | Danny Herrera | Kerry Wood | 160 | 206 | -46 |
| 2010-05-24 | vs CHA | 43 | L 2-7 | 16-27 | 5 | 10,166 | Justin Masterson | John Danks | John Danks | Justin Masterson | | 162 | 213 | -51 |
| 2010-05-25 | vs CHA | 44 | W 7-3 | 17-27 | 5 | 14,441 | Mitch Talbot | Jake Peavy | Mitch Talbot | Jake Peavy | | 169 | 216 | -47 |
| 2010-05-26 | vs CHA | 45 | L 4-5 | 17-28 | 5 | 18,109 | Jake Westbrook | Mark Buehrle | Tony Pena | Jake Westbrook | | 173 | 221 | -48 |
| 2010-05-28 | @ NYA | 46 | L 2-8 | 17-29 | 5 | 44,634 | Fausto Carmona | Phil Hughes | Phil Hughes | Fausto Carmona | | 175 | 229 | -54 |
| 2010-05-29 | @ NYA | 47 | W 13-11 | 18-29 | 5 | 46,599 | David Huff | CC Sabathia | Rafael Perez | Joba Chamberlain | Kerry Wood | 188 | 240 | -52 |
| 2010-05-30 | @ NYA | 48 | L 3-7 | 18-30 | 5 | 45,706 | Justin Masterson | A.J. Burnett | A.J. Burnett | Tony Sipp | | 191 | 247 | -56 |
| 2010-05-31 | @ NYA | 49 | L 2-11 | 19-30 | 4 | 44,976 | Mitch Talbot | Andy Pettitte | Andy Pettitte | Mitch Talbot | | 193 | 258 | -65 |
| 2010-06-01 | @ DET | 50 | W 3-2 | 20-30 | 4 | 19,446 | Jake Westbrook | Jeremy Bonderman | Jake Westbrook | Jeremy Bonderman | Kerry Wood | 196 | 260 | -64 |
| 2010-06-02 | @ DET | 51 | L 0-3 | 20-31 | 4 | 17,738 | Fausto Carmona | Armando Galarraga | Armando Galarraga | Fausto Carmona | | 196 | 263 | -67 |
| 2010-06-03 | @ DET | 52 | L 6-12 | 21-31 | 4 | 28,169 | David Huff | Rick Porcello | Brad Thomas | Hector Ambriz | | 202 | 275 | -73 |
| 2010-06-04 | @ CHA | 53 | W 10-1 | 22-31 | 4 | 20,713 | Justin Masterson | John Danks | Justin Masterson | John Danks | | 212 | 276 | -64 |
| 2010-06-05 | @ CHA | 54 | W 3-1 | 23-31 | 4 | 30,864 | Mitch Talbot | Jake Peavy | Mitch Talbot | Jake Peavy | Kerry Wood | 215 | 277 | -62 |
| 2010-06-06 | @ CHA | 55 | L 7-8 | 23-32 | 4 | 27,577 | Jake Westbrook | Mark Buehrle | J.J. Putz | Tony Sipp | Bobby Jenks | 222 | 285 | -63 |
| 2010-06-07 | vs BOS | 56 | L 1-4 | 23-33 | 4 | 14,758 | Fausto Carmona | Daisuke Matsuzaka | Daisuke Matsuzaka | Fausto Carmona | | 223 | 289 | -66 |
| 2010-06-08 | vs BOS | 57 | L 2-3 | 23-34 | 4 | 15,462 | David Huff | Tim Wakefield | Tim Wakefield | David Huff | Daniel Bard | 225 | 292 | -67 |
| 2010-06-09 | vs BOS | 58 | W 11-0 | 24-34 | 4 | 14,022 | Justin Masterson | Clay Buchholz | Justin Masterson | Clay Buchholz | | 236 | 292 | -56 |
| 2010-06-10 | vs BOS | 59 | W 8-7 | 25-34 | 4 | 20,446 | Mitch Talbot | Jon Lester | Kerry Wood | Daniel Bard | | 244 | 299 | -55 |
| 2010-06-11 | vs WAS | 60 | W 7-2 | 26-34 | 4 | 22,041 | Jake Westbrook | Luis Atilano | Jake Westbrook | Luis Atilano | Chris Perez | 251 | 301 | -50 |
| 2010-06-12 | vs WAS | 61 | W 7-1 | 27-34 | 4 | 19,484 | Fausto Carmona | J.D. Martin | Fausto Carmona | J.D. Martin | | 258 | 302 | -44 |
| 2010-06-13 | vs WAS | 62 | L 4-9 | 27-35 | 4 | 32,876 | David Huff | Stephen Strasburg | Stephen Strasburg | David Huff | | 262 | 311 | -49 |
| 2010-06-15 | vs NYN | 63 | L 6-7 | 27-36 | 4 | 12,882 | Justin Masterson | Johan Santana | Johan Santana | Justin Masterson | Francisco Rodriguez | 268 | 318 | -50 |
| 2010-06-16 | vs NYN | 64 | L 4-8 | 27-37 | 4 | 14,246 | Mitch Talbot | Jonathon Niese | Jonathon Niese | Mitch Talbot | | 272 | 326 | -54 |
| 2010-06-17 | vs NYN | 65 | L 4-6 | 27-38 | 5 | 14,339 | Jake Westbrook | R.A. Dickey | R.A. Dickey | Jake Westbrook | Francisco Rodriguez | 276 | 332 | -56 |
| 2010-06-18 | @ PIT | 66 | W 4-3 | 28-38 | 4 | 28,478 | Fausto Carmona | Paul Maholm | Fausto Carmona | Paul Maholm | Kerry Wood | 280 | 335 | -55 |
| 2010-06-19 | @ PIT | 67 | L 4-6 | 28-39 | 4 | 38,008 | David Huff | Jeff Karstens | Jeff Karstens | David Huff | Octavio Dotel | 284 | 341 | -57 |
| 2010-06-20 | @ PIT | 68 | L 3-5 | 28-40 | 4 | 29,845 | Justin Masterson | Brad Lincoln | Brendan Donnelly | Jensen Lewis | Octavio Dotel | 287 | 346 | -59 |
| 2010-06-22 | @ PHI | 69 | L 1-2 | 28-41 | 4 | 44,836 | Mitch Talbot | Jamie Moyer | Jamie Moyer | Mitch Talbot | Brad Lidge | 288 | 348 | -60 |
| 2010-06-23 | @ PHI | 70 | L 6-7 | 28-42 | 4 | 44,510 | Jake Westbrook | Kyle Kendrick | J.C. Romero | Kerry Wood | | 294 | 355 | -61 |
| 2010-06-24 | @ PHI | 71 | L 3-12 | 29-42 | 4 | 45,085 | Fausto Carmona | Joe Blanton | Joe Blanton | Fausto Carmona | | 297 | 367 | -70 |
| 2010-06-25 | @ CIN | 72 | L 3-10 | 30-42 | 4 | 32,844 | Aaron Laffey | Aaron Harang | Aaron Harang | Aaron Laffey | | 300 | 377 | -77 |
| 2010-06-26 | @ CIN | 73 | L 4-6 | 30-43 | 4 | 37,757 | Justin Masterson | Sam LeCure | Danny Herrera | Justin Masterson | Francisco Cordero | 304 | 383 | -79 |
| 2010-06-27 | @ CIN | 74 | W 5-3 | 31-43 | 4 | 25,877 | Mitch Talbot | Bronson Arroyo | Mitch Talbot | Bronson Arroyo | Kerry Wood | 309 | 386 | -77 |
| 2010-06-28 | vs TOR | 75 | W 2-1 | 32-43 | 4 | 11,577 | Jake Westbrook | Ricky Romero | Jake Westbrook | Ricky Romero | Kerry Wood | 311 | 387 | -76 |
| 2010-06-29 | vs TOR | 76 | W 5-4 | 33-43 | 4 | 11,401 | Fausto Carmona | Brandon Morrow | Fausto Carmona | Brandon Morrow | Kerry Wood | 316 | 391 | -75 |
| 2010-06-30 | vs TOR | 77 | W 3-1 | 34-43 | 4 | 12,109 | Aaron Laffey | Jesse Litsch | Aaron Laffey | Jesse Litsch | Chris Perez | 319 | 392 | -73 |
| 2010-07-01 | vs TOR | 78 | W 6-1 | 35-43 | 4 | 16,859 | Justin Masterson | Shaun Marcum | Justin Masterson | Shaun Marcum | Frank Herrmann | 325 | 393 | -68 |
| 2010-07-02 | vs OAK | 79 | L 0-3 | 35-44 | 4 | 18,629 | Mitch Talbot | Gio Gonzalez | Gio Gonzalez | Mitch Talbot | Andrew Bailey | 325 | 396 | -71 |
| 2010-07-03 | vs OAK | 80 | W 5-4 | 36-44 | 4 | 25,483 | Jake Westbrook | Clayton Mortenson | Tony Sipp | Craig Breslow | | 330 | 400 | -70 |
| 2010-07-04 | vs OAK | 81 | L 1-3 | 36-45 | 4 | 13,940 | Fausto Carmona | Vin Mazzaro | Vin Mazzaro | Fausto Carmona | Andrew Bailey | 331 | 403 | -72 |
| 2010-07-05 | @ TEX | 82 | W 9-3 | 37-45 | 4 | 25,165 | Aaron Laffey | Omar Beltre | Joe Smith | Omar Beltre | | 340 | 406 | -66 |
| 2010-07-06 | @ TEX | 83 | L 1-12 | 37-46 | 4 | 20,428 | Justin Masterson | C.J. Wilson | C.J. Wilson | Justin Masterson | | 341 | 418 | -77 |
| 2010-07-07 | @ TEX | 84 | L 3-4 | 37-47 | 4 | 24,427 | Mitch Talbot | Colby Lewis | Colby Lewis | Mitch Talbot | Neftali Feliz | 344 | 422 | -78 |
| 2010-07-08 | @ TBA | 85 | L 2-5 | 37-48 | 4 | 16,892 | Jake Westbrook | Wade Davis | Wade Davis | Jake Westbrook | Dan Wheeler | 346 | 427 | -81 |
| 2010-07-09 | @ TBA | 86 | W 9-3 | 38-48 | 4 | 23,116 | Fausto Carmona | James Shields | Fausto Carmona | James Shields | | 355 | 430 | -75 |
| 2010-07-10 | @ TBA | 87 | L 0-4 | 38-49 | 4 | 20,091 | Aaron Laffey | Matt Garza | Matt Garza | Aaron Laffey | | 355 | 434 | -79 |
| 2010-07-11 | @ TBA | 88 | L 5-6 | 38-50 | 4 | 24,687 | Justin Masterson | Jeff Niemann | Andy Sonnanstine | Kerry Wood | | 360 | 440 | -80 |
| 2010-07-16 | vs DET | 89 | W 8-2 | 39-50 | 4 | 22,295 | Jake Westbrook | Max Scherzer | Jake Westbrook | Max Scherzer | | 368 | 442 | -74 |
| 2010-07-17 | vs DET | 90 | W 4-3 | 40-50 | 6 | 20,090 | Fausto Carmona | Justin Verlander | Fausto Carmona | Phil Coke | Chris Perez | 372 | 445 | -73 |
| 2010-07-17 | vs DET | 91 | W 2-1 | 40-50 | 6 | 20,902 | Mitch Talbot | Rick Porcello | Rafael Perez | Robbie Weinhart | | 374 | 446 | -72 |
| 2010-07-18 | vs DET | 92 | W 7-2 | 42-50 | 4 | 19,102 | Jeanmar Gomez | Andrew Oliver | Jeanmar Gomez | Andrew Oliver | | 381 | 448 | -67 |
| 2010-07-19 | @ MIN | 93 | W 10-4 | 42-51 | 4 | 40,853 | Aaron Laffey | Scott Baker | Aaron Laffey | Scott Baker | | 391 | 452 | -61 |
| 2010-07-20 | @ MIN | 94 | W 4-3 | 43-51 | 4 | 40,745 | Justin Masterson | Kevin Slowey | Rafael Perez | Jose Mijares | Chris Perez | 395 | 455 | -60 |
| 2010-07-21 | @ MIN | 95 | L 0-6 | 43-52 | 4 | 40,799 | Jake Westbrook | Francisco Liriano | Francisco Liriano | Jake Westbrook | | 395 | 461 | -66 |
| 2010-07-23 | vs TBA | 96 | W 3-1 | 44-52 | 4 | 16,904 | Fausto Carmona | Jeff Niemann | Fausto Carmona | Jeff Niemann | Tony Sipp | 398 | 462 | -64 |
| 2010-07-24 | vs TBA | 97 | L 3-6 | 44-53 | 4 | 17,221 | Mitch Talbot | David Price | David Price | Mitch Talbot | Rafael Soriano | 401 | 468 | -67 |
| 2010-07-25 | vs TBA | 98 | L 2-4 | 44-54 | 5 | 13,410 | Justin Masterson | Wade Davis | Wade Davis | Justin Masterson | Rafael Soriano | 403 | 472 | -69 |
| 2010-07-26 | vs NYA | 99 | L 2-3 | 44-55 | 4 | 27,224 | Jake Westbrook | Javier Vazquez | Javier Vazquez | Jake Westbrook | Mariano Rivera | 405 | 475 | -70 |
| 2010-07-27 | vs NYA | 100 | W 4-1 | 45-55 | 4 | 27,416 | Josh Tomlin | CC Sabathia | Josh Tomlin | CC Sabathia | Chris Perez | 409 | 476 | -67 |
| 2010-07-28 | vs NYA | 101 | L 0-8 | 45-56 | 4 | 22,965 | Fausto Carmona | A.J. Burnett | A.J. Burnett | Fausto Carmona | | 409 | 484 | -75 |
| 2010-07-29 | vs NYA | 102 | L 4-11 | 46-56 | 4 | 34,455 | Mitch Talbot | Dustin Moseley | Dustin Moseley | Frank Herrmann | | 413 | 495 | -82 |
| 2010-07-30 | @ TOR | 103 | L 1-8 | 46-57 | 4 | 20,228 | Justin Masterson | Shaun Marcum | Shaun Marcum | Justin Masterson | | 414 | 503 | -89 |
| 2010-07-31 | @ TOR | 104 | W 2-1 | 47-57 | 4 | 22,663 | Josh Tomlin | Brett Cecil | Jensen Lewis | Brian Tallet | Chris Perez | 416 | 504 | -88 |
| 2010-08-01 | @ TOR | 105 | W 5-4 | 48-57 | 4 | 21,797 | Jeanmar Gomez | Jesse Litsch | Jeanmar Gomez | Jesse Litsch | Chris Perez | 421 | 508 | -87 |
| 2010-08-02 | @ BOS | 106 | W 6-5 | 49-57 | 4 | 37,931 | Fausto Carmona | John Lackey | Fausto Carmona | John Lackey | Chris Perez | 427 | 513 | -86 |
| 2010-08-03 | @ BOS | 107 | L 1-3 | 49-58 | 6 | 37,714 | David Huff | Josh Beckett | Josh Beckett | David Huff | Jonathan Papelbon | 428 | 516 | -88 |
| 2010-08-04 | @ BOS | 108 | W 9-1 | 50-58 | 4 | 37,902 | Justin Masterson | Jon Lester | Justin Masterson | Jon Lester | | 437 | 517 | -80 |
| 2010-08-05 | @ BOS | 109 | L 2-6 | 50-59 | 4 | 38,102 | Josh Tomlin | Daisuke Matsuzaka | Daisuke Matsuzaka | Josh Tomlin | Jonathan Papelbon | 439 | 523 | -84 |
| 2010-08-06 | vs MIN | 110 | W 7-6 | 51-59 | 4 | 25,275 | Jeanmar Gomez | Francisco Liriano | Chris Perez | Matt Guerrier | | 446 | 529 | -83 |
| 2010-08-07 | vs MIN | 111 | L 2-7 | 51-60 | 4 | 27,638 | Fausto Carmona | Carl Pavano | Carl Pavano | Fausto Carmona | | 448 | 536 | -88 |
| 2010-08-08 | vs MIN | 112 | L 4-5 | 51-61 | 4 | 17,427 | David Huff | Brian Duensing | Brian Duensing | David Huff | Matt Capps | 452 | 541 | -89 |
| 2010-08-10 | vs BAL | 113 | L 8-14 | 52-61 | 4 | 13,541 | Justin Masterson | Jake Arrieta | Jake Arrieta | Justin Masterson | | 460 | 555 | -95 |
| 2010-08-11 | vs BAL | 114 | L 1-3 | 52-62 | 4 | 11,155 | Josh Tomlin | Brad Bergesen | Brad Bergesen | Josh Tomlin | | 461 | 558 | -97 |
| 2010-08-12 | vs BAL | 115 | W 4-1 | 53-62 | 4 | 14,533 | Jeanmar Gomez | Kevin Millwood | Jeanmar Gomez | Kevin Millwood | Chris Perez | 465 | 559 | -94 |
| 2010-08-13 | vs SEA | 116 | L 2-3 | 53-63 | 4 | 26,424 | Fausto Carmona | David Pauley | David Pauley | Fausto Carmona | David Aardsma | 467 | 562 | -95 |
| 2010-08-14 | vs SEA | 117 | L 3-9 | 53-64 | 4 | 25,980 | Mitch Talbot | Jason Vargas | Jason Vargas | Mitch Talbot | | 470 | 571 | -101 |
| 2010-08-15 | vs SEA | 118 | W 9-1 | 54-64 | 4 | 14,888 | Justin Masterson | Felix Hernandez | Tony Sipp | Felix Hernandez | | 479 | 572 | -93 |
| 2010-08-17 | @ KCA | 119 | L 1-2 | 54-65 | 4 | 13,258 | Jeanmar Gomez | Zack Greinke | Zack Greinke | Jeanmar Gomez | Joakim Soria | 480 | 574 | -94 |
| 2010-08-18 | @ KCA | 120 | L 7-9 | 54-66 | 4 | 12,864 | Fausto Carmona | Bruce Chen | Bruce Chen | Fausto Carmona | Joakim Soria | 487 | 583 | -96 |
| 2010-08-19 | @ KCA | 121 | W 7-3 | 55-66 | 4 | 9,732 | Mitch Talbot | Kyle Davies | Rafael Perez | Blake Wood | Chris Perez | 494 | 586 | -92 |
| 2010-08-20 | @ DET | 122 | L 0-6 | 55-67 | 4 | 33,936 | Justin Masterson | Armando Galarraga | Armando Galarraga | Justin Masterson | | 494 | 592 | -98 |
| 2010-08-21 | @ DET | 123 | L 2-5 | 55-68 | 5 | 38,088 | Josh Tomlin | Max Scherzer | Max Scherzer | Josh Tomlin | Jose Valverde | 496 | 597 | -101 |
| 2010-08-22 | @ DET | 124 | L 1-8 | 55-69 | 4 | 35,104 | Jeanmar Gomez | Justin Verlander | Justin Verlander | Jeanmar Gomez | | 497 | 605 | -108 |
| 2010-08-24 | vs OAK | 125 | L 0-5 | 55-70 | 5 | 11,751 | Fausto Carmona | Gio Gonzalez | Gio Gonzalez | Fausto Carmona | | 497 | 610 | -113 |
| 2010-08-25 | vs OAK | 126 | L 1-6 | 55-71 | 5 | 10,514 | Mitch Talbot | Trevor Cahill | Trevor Cahill | Mitch Talbot | | 498 | 616 | -118 |
| 2010-08-26 | vs OAK | 127 | W 3-2 | 56-71 | 5 | 11,826 | Justin Masterson | Vin Mazzaro | Justin Masterson | Vin Mazzaro | Chris Perez | 501 | 618 | -117 |
| 2010-08-27 | vs KCA | 128 | W 15-4 | 56-72 | 5 | 17,631 | Josh Tomlin | Bryan Bullington | Josh Tomlin | Bryan Bullington | | 516 | 622 | -106 |
| 2010-08-28 | vs KCA | 129 | W 4-3 | 57-72 | 5 | 16,372 | Jeanmar Gomez | Zack Greinke | Chris Perez | Jesse Chavez | | 520 | 625 | -105 |
| 2010-08-29 | vs KCA | 130 | L 2-6 | 57-73 | 5 | 19,725 | Fausto Carmona | Bruce Chen | Bruce Chen | Fausto Carmona | | 522 | 631 | -109 |
| 2010-08-30 | vs CHA | 131 | L 6-10 | 58-73 | 5 | 10,663 | Mitch Talbot | Mark Buehrle | Scott Linebrink | Rafael Perez | | 528 | 641 | -113 |
| 2010-08-31 | vs CHA | 132 | L 3-4 | 58-74 | 5 | 12,006 | Justin Masterson | Edwin Jackson | Edwin Jackson | Joe Smith | Bobby Jenks | 531 | 645 | -114 |
| 2010-09-01 | vs CHA | 133 | L 4-6 | 58-75 | 5 | 12,563 | Carlos Carrasco | Freddy Garcia | Tony Pena | Justin Germano | Chris Sale | 535 | 651 | -116 |
| 2010-09-02 | @ SEA | 134 | W 6-3 | 59-75 | 5 | 17,269 | Josh Tomlin | Doug Fister | Josh Tomlin | Doug Fister | Chris Perez | 541 | 654 | -113 |
| 2010-09-03 | @ SEA | 135 | L 0-1 | 59-76 | 5 | 17,271 | Fausto Carmona | Lucas French | Lucas French | Fausto Carmona | David Aardsma | 541 | 655 | -114 |
| 2010-09-04 | @ SEA | 136 | W 4-2 | 60-76 | 5 | 25,108 | Mitch Talbot | David Pauley | Mitch Talbot | David Pauley | Chris Perez | 545 | 657 | -112 |
| 2010-09-05 | @ SEA | 137 | L 0-3 | 60-77 | 5 | 22,621 | Jeanmar Gomez | Felix Hernandez | Felix Hernandez | Jeanmar Gomez | David Aardsma | 545 | 660 | -115 |
| 2010-09-06 | @ ANA | 138 | W 3-2 | 61-77 | 4 | 39,107 | Carlos Carrasco | Dan Haren | Jensen Lewis | Fernando Rodney | Chris Perez | 548 | 662 | -114 |
| 2010-09-07 | @ ANA | 139 | W 6-1 | 62-77 | 4 | 38,619 | Justin Masterson | Trevor Bell | Justin Masterson | Trevor Bell | | 554 | 663 | -109 |
| 2010-09-08 | @ ANA | 140 | L 3-4 | 62-78 | 4 | 37,857 | Josh Tomlin | Scott Kazmir | Matt Palmer | Hector Ambriz | | 557 | 667 | -110 |
| 2010-09-10 | vs MIN | 141 | W 2-0 | 63-78 | 4 | 26,207 | Fausto Carmona | Carl Pavano | Fausto Carmona | Carl Pavano | | 559 | 667 | -108 |
| 2010-09-11 | vs MIN | 142 | L 0-1 | 63-79 | 4 | 24,972 | Carlos Carrasco | Nick Blackburn | Matt Guerrier | Justin Germano | Matt Capps | 559 | 668 | -109 |
| 2010-09-12 | vs MIN | 143 | L 2-6 | 63-80 | 5 | 22,988 | Mitch Talbot | Kevin Slowey | Kevin Slowey | Mitch Talbot | | 561 | 674 | -113 |
| 2010-09-14 | vs ANA | 144 | W 4-3 | 64-80 | 4 | 15,734 | Josh Tomlin | Scott Kazmir | Josh Tomlin | Scott Kazmir | Chris Perez | 565 | 677 | -112 |
| 2010-09-15 | vs ANA | 145 | L 0-7 | 64-81 | 4 | 10,183 | Jeanmar Gomez | Jered Weaver | Jered Weaver | Jeanmar Gomez | | 565 | 684 | -119 |
| 2010-09-16 | vs ANA | 146 | W 3-2 | 65-81 | 4 | 14,000 | Fausto Carmona | Ervin Santana | Rafael Perez | Bobby Cassevah | | 568 | 686 | -118 |
| 2010-09-17 | @ KCA | 147 | W 11-4 | 65-82 | 5 | 21,168 | Carlos Carrasco | Kyle Davies | Carlos Carrasco | Kyle Davies | | 579 | 690 | -111 |
| 2010-09-18 | @ KCA | 148 | W 6-4 | 66-82 | 4 | 18,112 | Justin Masterson | Sean O'Sullivan | Joe Smith | Sean O'Sullivan | Chris Perez | 585 | 694 | -109 |
| 2010-09-19 | @ KCA | 149 | L 4-6 | 66-83 | 5 | 17,803 | Josh Tomlin | Luke Hochevar | Luke Hochevar | Josh Tomlin | Joakim Soria | 589 | 700 | -111 |
| 2010-09-20 | @ MIN | 150 | L 3-9 | 66-84 | 5 | 39,228 | Jeanmar Gomez | Brian Duensing | Brian Duensing | Jeanmar Gomez | | 592 | 709 | -117 |
| 2010-09-21 | @ MIN | 151 | L 4-6 | 66-85 | 5 | 39,580 | Fausto Carmona | Scott Baker | Glen Perkins | Justin Masterson | Matt Capps | 596 | 715 | -119 |
| 2010-09-22 | @ MIN | 152 | L 1-5 | 66-86 | 5 | 40,139 | Carlos Carrasco | Nick Blackburn | Nick Blackburn | Carlos Carrasco | | 597 | 720 | -123 |
| 2010-09-23 | vs KCA | 153 | L 2-4 | 66-87 | 5 | 16,625 | Mitch Talbot | Sean O'Sullivan | Sean O'Sullivan | Mitch Talbot | Joakim Soria | 599 | 724 | -125 |
| 2010-09-24 | vs KCA | 154 | W 7-3 | 67-87 | 5 | 25,100 | Josh Tomlin | Luke Hochevar | Josh Tomlin | Luke Hochevar | | 606 | 727 | -121 |
| 2010-09-25 | vs KCA | 155 | W 7-1 | 68-87 | 5 | 19,746 | Jeanmar Gomez | Zack Greinke | Jeanmar Gomez | Zack Greinke | | 613 | 728 | -115 |
| 2010-09-26 | vs KCA | 156 | W 5-3 | 69-87 | 4 | 18,813 | Fausto Carmona | Bruce Chen | Rafael Perez | Rob Tejeda | Vinnie Pestano | 618 | 731 | -113 |
| 2010-09-27 | vs DET | 157 | W 6-3 | 70-87 | 4 | 10,161 | Carlos Carrasco | Armando Galarraga | Carlos Carrasco | Armando Galarraga | Chris Perez | 624 | 734 | -110 |
| 2010-09-29 | vs DET | 158 | W 4-0 | 71-87 | 6 | 0 | Mitch Talbot | Max Scherzer | Mitch Talbot | Max Scherzer | | 628 | 734 | -106 |
| 2010-09-29 | vs DET | 159 | W 4-3 | 71-87 | 6 | 12,227 | Josh Tomlin | Justin Verlander | Josh Tomlin | Justin Verlander | Chris Perez | 632 | 737 | -105 |
| 2010-10-01 | @ CHA | 160 | W 7-3 | 73-87 | 5 | 23,128 | Fausto Carmona | Tony Pena | Fausto Carmona | Tony Pena | | 639 | 740 | -101 |
| 2010-10-02 | @ CHA | 161 | L 2-6 | 73-88 | 4 | 23,702 | Carlos Carrasco | Mark Buehrle | Mark Buehrle | Carlos Carrasco | | 641 | 746 | -105 |
| 2010-10-03 | @ CHA | 162 | L 5-6 | 73-89 | 4 | 24,539 | Justin Germano | Edwin Jackson | Edwin Jackson | Justin Germano | Chris Sale | 646 | 752 | -106 |