| 2010-04-05 | @ TEX | 1 | L 4-5 | 0-1 | 2 | 50,299 | Shaun Marcum | Scott Feldman | Frank Francisco | Jason Frasor | | 4 | 5 | -1 |
| 2010-04-07 | @ TEX | 2 | W 7-4 | 1-1 | 3 | 22,890 | Brian Tallet | Rich Harden | Brian Tallet | Dustin Nippert | Jason Frasor | 11 | 9 | 2 |
| 2010-04-08 | @ TEX | 3 | W 3-1 | 2-1 | 2 | 14,707 | Ricky Romero | C.J. Wilson | Casey Janssen | Frank Francisco | Jason Frasor | 14 | 10 | 4 |
| 2010-04-09 | @ BAL | 4 | W 7-6 | 3-1 | 2 | 48,891 | Brandon Morrow | Brad Bergesen | Casey Janssen | Mike Gonzalez | Kevin Gregg | 21 | 16 | 5 |
| 2010-04-10 | @ BAL | 5 | W 3-0 | 4-1 | 1 | 21,148 | Dana Eveland | David Hernandez | Dana Eveland | David Hernandez | Jason Frasor | 24 | 16 | 8 |
| 2010-04-11 | @ BAL | 6 | W 5-2 | 5-1 | 1 | 22,499 | Shaun Marcum | Kevin Millwood | Casey Janssen | Kevin Millwood | Kevin Gregg | 29 | 18 | 11 |
| 2010-04-12 | vs CHA | 7 | L 7-8 | 5-2 | 1 | 46,321 | Brian Tallet | Jake Peavy | Matt Thornton | Jeremy Accardo | Bobby Jenks | 36 | 26 | 10 |
| 2010-04-13 | vs CHA | 8 | W 4-2 | 6-2 | 1 | 12,167 | Ricky Romero | Gavin Floyd | Ricky Romero | Gavin Floyd | Kevin Gregg | 40 | 28 | 12 |
| 2010-04-14 | vs CHA | 9 | L 1-11 | 6-3 | 2 | 10,610 | Brandon Morrow | John Danks | John Danks | Brandon Morrow | | 41 | 39 | 2 |
| 2010-04-15 | vs CHA | 10 | W 7-3 | 7-3 | 1 | 10,744 | Dana Eveland | Freddy Garcia | Dana Eveland | Freddy Garcia | | 48 | 42 | 6 |
| 2010-04-16 | vs ANA | 11 | L 5-7 | 7-4 | 3 | 14,779 | Shaun Marcum | Jered Weaver | Jered Weaver | Shaun Marcum | Fernando Rodney | 53 | 49 | 4 |
| 2010-04-17 | vs ANA | 12 | L 3-6 | 7-5 | 3 | 17,187 | Brian Tallet | Joe Saunders | Joe Saunders | Brian Tallet | Fernando Rodney | 56 | 55 | 1 |
| 2010-04-18 | vs ANA | 13 | L 1-3 | 7-6 | 3 | 14,246 | Ricky Romero | Ervin Santana | Ervin Santana | Ricky Romero | | 57 | 58 | -1 |
| 2010-04-19 | vs KCA | 14 | W 8-1 | 8-6 | 3 | 10,314 | Brandon Morrow | Brian Bannister | Brandon Morrow | Brian Bannister | | 65 | 59 | 6 |
| 2010-04-20 | vs KCA | 15 | W 4-3 | 9-6 | 3 | 10,565 | Dana Eveland | Kyle Davies | Shawn Camp | Kyle Davies | Kevin Gregg | 69 | 62 | 7 |
| 2010-04-21 | vs KCA | 16 | L 3-4 | 9-7 | 3 | 15,577 | Shaun Marcum | Zack Greinke | Rob Tejeda | Scott Downs | Joakim Soria | 72 | 66 | 6 |
| 2010-04-23 | @ TBA | 17 | W 6-5 | 10-7 | 3 | 22,056 | Brett Cecil | Matt Garza | Brett Cecil | Matt Garza | Kevin Gregg | 78 | 71 | 7 |
| 2010-04-24 | @ TBA | 18 | L 3-9 | 10-8 | 3 | 23,870 | Ricky Romero | Jeff Niemann | Dan Wheeler | Scott Downs | | 81 | 80 | 1 |
| 2010-04-25 | @ TBA | 19 | L 0-6 | 10-9 | 3 | 23,250 | Brandon Morrow | David Price | David Price | Brandon Morrow | | 81 | 86 | -5 |
| 2010-04-26 | vs BOS | 20 | L 12-13 | 10-10 | 3 | 13,847 | Dana Eveland | Josh Beckett | Scott Schoeneweis | Shawn Camp | Jonathan Papelbon | 93 | 99 | -6 |
| 2010-04-27 | vs BOS | 21 | L 1-2 | 10-11 | 4 | 14,776 | Shaun Marcum | Clay Buchholz | Clay Buchholz | Scott Downs | Ramon Ramirez | 94 | 101 | -7 |
| 2010-04-28 | vs BOS | 22 | L 0-2 | 10-12 | 4 | 15,276 | Brett Cecil | Jon Lester | Jon Lester | Brett Cecil | Jonathan Papelbon | 94 | 103 | -9 |
| 2010-04-29 | vs OAK | 23 | W 6-3 | 11-12 | 4 | 10,721 | Ricky Romero | Justin Duchscherer | Ricky Romero | Justin Duchscherer | Kevin Gregg | 100 | 106 | -6 |
| 2010-04-30 | vs OAK | 24 | W 10-2 | 11-13 | 4 | 12,722 | Brandon Morrow | Trevor Cahill | Brandon Morrow | Trevor Cahill | | 110 | 108 | 2 |
| 2010-05-01 | vs OAK | 25 | L 3-4 | 11-14 | 4 | 13,951 | Dana Eveland | Gio Gonzalez | Gio Gonzalez | Dana Eveland | Andrew Bailey | 113 | 112 | 1 |
| 2010-05-02 | vs OAK | 26 | W 9-3 | 12-14 | 4 | 14,725 | Shaun Marcum | Ben Sheets | Shaun Marcum | Ben Sheets | | 122 | 115 | 7 |
| 2010-05-03 | @ CLE | 27 | W 5-1 | 13-14 | 3 | 10,117 | Brett Cecil | Mitch Talbot | Brett Cecil | Mitch Talbot | | 127 | 116 | 11 |
| 2010-05-04 | @ CLE | 28 | W 8-5 | 14-14 | 3 | 10,387 | Ricky Romero | Jake Westbrook | Ricky Romero | Jensen Lewis | Kevin Gregg | 135 | 121 | 14 |
| 2010-05-05 | @ CLE | 29 | W 5-4 | 15-14 | 3 | 12,563 | Brandon Morrow | Fausto Carmona | Jason Frasor | Chris Perez | | 140 | 125 | 15 |
| 2010-05-06 | @ CHA | 30 | W 2-0 | 16-14 | 3 | 20,106 | Dana Eveland | John Danks | Dana Eveland | John Danks | Kevin Gregg | 142 | 125 | 17 |
| 2010-05-07 | @ CHA | 31 | W 7-4 | 17-14 | 3 | 20,072 | Shaun Marcum | Mark Buehrle | Scott Downs | J.J. Putz | | 149 | 129 | 20 |
| 2010-05-08 | @ CHA | 32 | L 3-7 | 17-15 | 3 | 24,945 | Brett Cecil | Jake Peavy | Jake Peavy | Brett Cecil | | 152 | 136 | 16 |
| 2010-05-09 | @ CHA | 33 | W 9-7 | 18-15 | 3 | 23,850 | Ricky Romero | Gavin Floyd | Jason Frasor | Bobby Jenks | Kevin Gregg | 161 | 143 | 18 |
| 2010-05-10 | @ BOS | 34 | L 6-7 | 18-16 | 4 | 37,332 | Brandon Morrow | John Lackey | John Lackey | Brandon Morrow | Jonathan Papelbon | 167 | 150 | 17 |
| 2010-05-11 | @ BOS | 35 | L 1-6 | 18-17 | 4 | 37,609 | Dana Eveland | Daisuke Matsuzaka | Daisuke Matsuzaka | Dana Eveland | | 168 | 156 | 12 |
| 2010-05-12 | @ BOS | 36 | W 3-2 | 19-17 | 5 | 37,198 | Shaun Marcum | Tim Wakefield | Shaun Marcum | Tim Wakefield | Kevin Gregg | 171 | 158 | 13 |
| 2010-05-14 | vs TEX | 37 | W 16-10 | 20-17 | 4 | 16,020 | Brett Cecil | Rich Harden | Josh Roenicke | Doug Mathis | | 187 | 168 | 19 |
| 2010-05-15 | vs TEX | 38 | W 6-0 | 21-17 | 3 | 15,945 | Ricky Romero | Scott Feldman | Ricky Romero | Scott Feldman | | 193 | 168 | 25 |
| 2010-05-16 | vs TEX | 39 | W 5-2 | 22-17 | 3 | 25,518 | Brandon Morrow | Colby Lewis | Brandon Morrow | Colby Lewis | Kevin Gregg | 198 | 170 | 28 |
| 2010-05-17 | vs MIN | 40 | L 3-8 | 22-18 | 3 | 13,892 | Dana Eveland | Kevin Slowey | Kevin Slowey | Dana Eveland | | 201 | 178 | 23 |
| 2010-05-18 | vs MIN | 41 | W 11-2 | 22-19 | 4 | 27,981 | Shaun Marcum | Carl Pavano | Shaun Marcum | Carl Pavano | | 212 | 180 | 32 |
| 2010-05-19 | @ SEA | 42 | W 3-2 | 23-19 | 4 | 19,208 | Brett Cecil | Doug Fister | Brett Cecil | Doug Fister | Kevin Gregg | 215 | 182 | 33 |
| 2010-05-20 | @ SEA | 43 | L 3-4 | 23-20 | 4 | 20,452 | Ricky Romero | Jason Vargas | Shawn Kelley | Kevin Gregg | | 218 | 186 | 32 |
| 2010-05-21 | @ ARI | 44 | L 6-8 | 23-21 | 4 | 19,531 | Brandon Morrow | Dan Haren | Dan Haren | Brandon Morrow | Chad Qualls | 224 | 194 | 30 |
| 2010-05-22 | @ ARI | 45 | L 5-8 | 23-22 | 4 | 32,746 | Dana Eveland | Edwin Jackson | Edwin Jackson | Dana Eveland | Chad Qualls | 229 | 202 | 27 |
| 2010-05-23 | @ ARI | 46 | W 12-4 | 23-23 | 4 | 23,148 | Shaun Marcum | Billy Buckner | Shaun Marcum | Billy Buckner | | 241 | 206 | 35 |
| 2010-05-24 | @ ANA | 47 | W 6-0 | 24-23 | 4 | 35,826 | Brett Cecil | Joe Saunders | Brett Cecil | Joe Saunders | | 247 | 206 | 41 |
| 2010-05-25 | @ ANA | 48 | L 3-8 | 24-24 | 4 | 43,174 | Ricky Romero | Ervin Santana | Ervin Santana | Ricky Romero | | 250 | 214 | 36 |
| 2010-05-26 | @ ANA | 49 | L 5-6 | 24-25 | 4 | 34,504 | Brandon Morrow | Joel Pineiro | Brian Fuentes | Scott Downs | | 255 | 220 | 35 |
| 2010-05-28 | vs BAL | 50 | W 5-0 | 25-25 | 4 | 16,360 | Shaun Marcum | Kevin Millwood | Shaun Marcum | Kevin Millwood | | 260 | 220 | 40 |
| 2010-05-29 | vs BAL | 51 | W 5-2 | 26-25 | 4 | 16,194 | Brett Cecil | Chris Tillman | Brett Cecil | Jason Berken | Kevin Gregg | 265 | 222 | 43 |
| 2010-05-30 | vs BAL | 52 | W 6-1 | 27-25 | 4 | 15,878 | Ricky Romero | Jeremy Guthrie | Ricky Romero | Jeremy Guthrie | | 271 | 223 | 48 |
| 2010-05-31 | vs TBA | 53 | W 3-2 | 28-25 | 4 | 11,335 | Brandon Morrow | Matt Garza | Brandon Morrow | Matt Garza | Kevin Gregg | 274 | 225 | 49 |
| 2010-06-01 | vs TBA | 54 | L 6-7 | 28-26 | 4 | 13,439 | Brian Tallet | Jeff Niemann | Grant Balfour | Kevin Gregg | Rafael Soriano | 280 | 232 | 48 |
| 2010-06-02 | vs TBA | 55 | L 3-7 | 28-27 | 4 | 13,517 | Shaun Marcum | David Price | David Price | Shaun Marcum | | 283 | 239 | 44 |
| 2010-06-04 | vs NYA | 56 | W 6-1 | 29-27 | 4 | 30,089 | Brett Cecil | A.J. Burnett | Brett Cecil | A.J. Burnett | | 289 | 240 | 49 |
| 2010-06-05 | vs NYA | 57 | W 3-2 | 30-27 | 4 | 37,165 | Ricky Romero | Andy Pettitte | Casey Janssen | Chad Gaudin | | 292 | 242 | 50 |
| 2010-06-06 | vs NYA | 58 | L 3-4 | 30-28 | 4 | 33,622 | Brandon Morrow | Javier Vazquez | Javier Vazquez | Scott Downs | Mariano Rivera | 295 | 246 | 49 |
| 2010-06-08 | @ TBA | 59 | L 0-9 | 30-29 | 4 | 12,937 | Brian Tallet | Jeff Niemann | Jeff Niemann | Brian Tallet | | 295 | 255 | 40 |
| 2010-06-09 | @ TBA | 60 | L 1-10 | 30-30 | 4 | 15,886 | Shaun Marcum | David Price | David Price | Shaun Marcum | | 296 | 265 | 31 |
| 2010-06-10 | @ TBA | 61 | W 3-2 | 31-30 | 4 | 13,675 | Brett Cecil | Wade Davis | Brett Cecil | Wade Davis | Kevin Gregg | 299 | 267 | 32 |
| 2010-06-11 | @ COL | 62 | L 3-5 | 31-31 | 4 | 31,101 | Ricky Romero | Ubaldo Jimenez | Ubaldo Jimenez | Ricky Romero | | 302 | 272 | 30 |
| 2010-06-12 | @ COL | 63 | L 0-1 | 31-32 | 4 | 26,304 | Brandon Morrow | Jason Hammel | Jason Hammel | Brandon Morrow | Manuel Corpas | 302 | 273 | 29 |
| 2010-06-13 | @ COL | 64 | L 3-10 | 32-32 | 4 | 32,084 | Jesse Litsch | Jeff Francis | Jeff Francis | Jesse Litsch | | 305 | 283 | 22 |
| 2010-06-14 | @ SDN | 65 | W 6-3 | 33-32 | 4 | 16,542 | Shaun Marcum | Jon Garland | Shaun Marcum | Jon Garland | Kevin Gregg | 311 | 286 | 25 |
| 2010-06-15 | @ SDN | 66 | L 2-8 | 33-33 | 4 | 15,266 | Brett Cecil | Mat Latos | Mat Latos | Brett Cecil | | 313 | 294 | 19 |
| 2010-06-16 | @ SDN | 67 | W 7-1 | 34-33 | 4 | 16,050 | Ricky Romero | Kevin Correia | Ricky Romero | Kevin Correia | | 320 | 295 | 25 |
| 2010-06-18 | vs SFN | 68 | W 3-2 | 35-33 | 4 | 18,667 | Brandon Morrow | Barry Zito | Scott Downs | Barry Zito | Kevin Gregg | 323 | 297 | 26 |
| 2010-06-19 | vs SFN | 69 | W 3-0 | 36-33 | 4 | 20,666 | Jesse Litsch | Matt Cain | Shawn Camp | Matt Cain | Kevin Gregg | 326 | 297 | 29 |
| 2010-06-20 | vs SFN | 70 | L 6-9 | 36-34 | 4 | 21,431 | Shaun Marcum | Jonathan Sanchez | Denny Bautista | Brian Tallet | Brian Wilson | 332 | 306 | 26 |
| 2010-06-22 | vs SLN | 71 | L 4-9 | 36-35 | 4 | 16,830 | Brett Cecil | Jaime Garcia | Jaime Garcia | Brett Cecil | | 336 | 315 | 21 |
| 2010-06-23 | vs SLN | 72 | L 0-1 | 36-36 | 4 | 14,079 | Ricky Romero | Chris Carpenter | Chris Carpenter | Kevin Gregg | Ryan Franklin | 336 | 316 | 20 |
| 2010-06-24 | vs SLN | 73 | W 5-0 | 37-36 | 4 | 12,392 | Brandon Morrow | Adam Wainwright | Brandon Morrow | Adam Wainwright | | 341 | 316 | 25 |
| 2010-06-25 | vs PHI | 74 | L 0-9 | 37-37 | 4 | 43,076 | Jesse Litsch | Roy Halladay | Roy Halladay | Jesse Litsch | | 341 | 325 | 16 |
| 2010-06-26 | vs PHI | 75 | W 5-1 | 38-37 | 4 | 44,426 | Shaun Marcum | Cole Hamels | Shaun Marcum | Cole Hamels | | 346 | 326 | 20 |
| 2010-06-27 | vs PHI | 76 | L 2-11 | 39-37 | 4 | 42,571 | Brett Cecil | Jamie Moyer | Jamie Moyer | Brett Cecil | | 348 | 337 | 11 |
| 2010-06-28 | @ CLE | 77 | L 1-2 | 39-38 | 4 | 11,577 | Ricky Romero | Jake Westbrook | Jake Westbrook | Ricky Romero | Kerry Wood | 349 | 339 | 10 |
| 2010-06-29 | @ CLE | 78 | L 4-5 | 39-39 | 4 | 11,401 | Brandon Morrow | Fausto Carmona | Fausto Carmona | Brandon Morrow | Kerry Wood | 353 | 344 | 9 |
| 2010-06-30 | @ CLE | 79 | L 1-3 | 39-40 | 4 | 12,109 | Jesse Litsch | Aaron Laffey | Aaron Laffey | Jesse Litsch | Chris Perez | 354 | 347 | 7 |
| 2010-07-01 | @ CLE | 80 | L 1-6 | 39-41 | 4 | 16,859 | Shaun Marcum | Justin Masterson | Justin Masterson | Shaun Marcum | Frank Herrmann | 355 | 353 | 2 |
| 2010-07-02 | @ NYA | 81 | W 6-1 | 40-41 | 4 | 45,792 | Brett Cecil | A.J. Burnett | Jason Frasor | David Robertson | | 361 | 354 | 7 |
| 2010-07-03 | @ NYA | 82 | L 3-11 | 41-41 | 4 | 46,364 | Ricky Romero | Andy Pettitte | Andy Pettitte | Ricky Romero | | 364 | 365 | -1 |
| 2010-07-04 | @ NYA | 83 | L 6-7 | 41-42 | 4 | 46,810 | Brandon Morrow | Phil Hughes | David Robertson | David Purcey | | 370 | 372 | -2 |
| 2010-07-06 | vs MIN | 84 | L 6-7 | 41-43 | 4 | 15,072 | Jesse Litsch | Carl Pavano | Jose Mijares | Jason Frasor | Jon Rauch | 376 | 379 | -3 |
| 2010-07-07 | vs MIN | 85 | W 6-5 | 42-43 | 4 | 14,886 | Marc Rzepczynski | Kevin Slowey | Scott Downs | Matt Guerrier | Kevin Gregg | 382 | 384 | -2 |
| 2010-07-08 | vs MIN | 86 | W 8-1 | 43-43 | 4 | 15,601 | Brett Cecil | Scott Baker | Brett Cecil | Scott Baker | | 390 | 385 | 5 |
| 2010-07-09 | vs BOS | 87 | L 3-14 | 44-43 | 4 | 27,567 | Ricky Romero | Jon Lester | Jon Lester | Ricky Romero | | 393 | 399 | -6 |
| 2010-07-10 | vs BOS | 88 | W 9-5 | 45-43 | 4 | 35,037 | Brandon Morrow | John Lackey | Shawn Camp | John Lackey | Kevin Gregg | 402 | 404 | -2 |
| 2010-07-11 | vs BOS | 89 | L 2-3 | 45-44 | 4 | 26,062 | Jesse Litsch | Daisuke Matsuzaka | Daisuke Matsuzaka | Jesse Litsch | Jonathan Papelbon | 404 | 407 | -3 |
| 2010-07-16 | @ BAL | 90 | W 4-2 | 46-44 | 4 | 18,120 | Ricky Romero | Brad Bergesen | Ricky Romero | Brad Bergesen | Kevin Gregg | 408 | 409 | -1 |
| 2010-07-17 | @ BAL | 91 | W 3-2 | 47-44 | 4 | 28,518 | Brandon Morrow | Jeremy Guthrie | Brandon Morrow | Jason Berken | Shawn Camp | 411 | 411 | 0 |
| 2010-07-18 | @ BAL | 92 | W 10-1 | 48-44 | 4 | 14,032 | Shaun Marcum | Brian Matusz | Shaun Marcum | Brian Matusz | | 421 | 412 | 9 |
| 2010-07-19 | @ KCA | 93 | L 4-5 | 48-45 | 4 | 12,968 | Brett Cecil | Kyle Davies | Kyle Farnsworth | Kevin Gregg | | 425 | 417 | 8 |
| 2010-07-20 | @ KCA | 94 | W 13-1 | 49-45 | 4 | 18,865 | Jesse Litsch | Anthony Lerew | Jesse Litsch | Anthony Lerew | | 438 | 418 | 20 |
| 2010-07-21 | @ KCA | 95 | L 2-5 | 49-46 | 4 | 15,285 | Marc Rzepczynski | Zack Greinke | Zack Greinke | Marc Rzepczynski | Joakim Soria | 440 | 423 | 17 |
| 2010-07-22 | @ DET | 96 | L 2-5 | 49-47 | 4 | 34,476 | Ricky Romero | Justin Verlander | Justin Verlander | Ricky Romero | Jose Valverde | 442 | 428 | 14 |
| 2010-07-24 | @ DET | 97 | W 3-2 | 50-47 | 4 | 39,391 | Shaun Marcum | Rick Porcello | Shaun Marcum | Rick Porcello | Kevin Gregg | 445 | 430 | 15 |
| 2010-07-25 | @ DET | 98 | W 5-3 | 51-48 | 5 | 38,526 | Brett Cecil | Armando Galarraga | Scott Downs | Jose Valverde | Kevin Gregg | 450 | 433 | 17 |
| 2010-07-25 | @ DET | 99 | L 5-6 | 51-48 | 5 | 37,093 | Jesse Litsch | Jeremy Bonderman | Phil Coke | Jason Frasor | Jose Valverde | 455 | 439 | 16 |
| 2010-07-26 | vs BAL | 100 | W 9-5 | 52-48 | 4 | 17,422 | Brandon Morrow | Brad Bergesen | Brandon Morrow | Brad Bergesen | David Purcey | 464 | 444 | 20 |
| 2010-07-27 | vs BAL | 101 | W 8-2 | 53-48 | 4 | 16,862 | Ricky Romero | Kevin Millwood | Ricky Romero | Kevin Millwood | | 472 | 446 | 26 |
| 2010-07-28 | vs BAL | 102 | W 5-0 | 54-48 | 4 | 17,041 | Brad Mills | Jeremy Guthrie | Brad Mills | Jeremy Guthrie | | 477 | 446 | 31 |
| 2010-07-30 | vs CLE | 103 | W 8-1 | 55-48 | 4 | 20,228 | Shaun Marcum | Justin Masterson | Shaun Marcum | Justin Masterson | | 485 | 447 | 38 |
| 2010-07-31 | vs CLE | 104 | L 1-2 | 55-49 | 4 | 22,663 | Brett Cecil | Josh Tomlin | Jensen Lewis | Brian Tallet | Chris Perez | 486 | 449 | 37 |
| 2010-08-01 | vs CLE | 105 | L 4-5 | 55-50 | 4 | 21,797 | Jesse Litsch | Jeanmar Gomez | Jeanmar Gomez | Jesse Litsch | Chris Perez | 490 | 454 | 36 |
| 2010-08-02 | @ NYA | 106 | W 8-6 | 56-50 | 4 | 47,034 | Brandon Morrow | A.J. Burnett | Brandon Morrow | A.J. Burnett | Kevin Gregg | 498 | 460 | 38 |
| 2010-08-03 | @ NYA | 107 | W 8-2 | 57-50 | 4 | 46,480 | Ricky Romero | Dustin Moseley | Ricky Romero | Dustin Moseley | | 506 | 462 | 44 |
| 2010-08-04 | @ NYA | 108 | L 1-5 | 57-51 | 4 | 47,659 | Shaun Marcum | Phil Hughes | Phil Hughes | Shaun Marcum | | 507 | 467 | 40 |
| 2010-08-06 | vs TBA | 109 | W 2-1 | 58-51 | 4 | 22,520 | Brett Cecil | Matt Garza | Brett Cecil | Matt Garza | Kevin Gregg | 509 | 468 | 41 |
| 2010-08-07 | vs TBA | 110 | W 17-11 | 59-51 | 4 | 24,168 | Brad Mills | James Shields | Brian Tallet | James Shields | | 526 | 479 | 47 |
| 2010-08-08 | vs TBA | 111 | W 1-0 | 60-51 | 4 | 22,313 | Brandon Morrow | Andy Sonnanstine | Brandon Morrow | Andy Sonnanstine | | 527 | 479 | 48 |
| 2010-08-10 | vs BOS | 112 | L 5-7 | 60-52 | 4 | 27,690 | Ricky Romero | Daisuke Matsuzaka | Felix Doubront | Shawn Camp | Jonathan Papelbon | 532 | 486 | 46 |
| 2010-08-11 | vs BOS | 113 | L 1-10 | 60-53 | 4 | 28,308 | Shaun Marcum | Clay Buchholz | Clay Buchholz | Shaun Marcum | | 533 | 496 | 37 |
| 2010-08-12 | vs BOS | 114 | W 6-5 | 61-53 | 4 | 36,271 | Brad Mills | John Lackey | Kevin Gregg | Jonathan Papelbon | | 539 | 501 | 38 |
| 2010-08-13 | @ ANA | 115 | W 3-0 | 62-53 | 4 | 40,606 | Marc Rzepczynski | Scott Kazmir | Marc Rzepczynski | Scott Kazmir | Kevin Gregg | 542 | 501 | 41 |
| 2010-08-14 | @ ANA | 116 | L 2-7 | 62-54 | 4 | 42,059 | Brett Cecil | Ervin Santana | Ervin Santana | Brett Cecil | | 544 | 508 | 36 |
| 2010-08-15 | @ ANA | 117 | W 4-1 | 63-54 | 4 | 38,138 | Ricky Romero | Dan Haren | Ricky Romero | Dan Haren | Kevin Gregg | 548 | 509 | 39 |
| 2010-08-16 | @ OAK | 118 | W 3-1 | 64-54 | 4 | 10,136 | Shaun Marcum | Brett Anderson | Shaun Marcum | Brett Anderson | | 551 | 510 | 41 |
| 2010-08-17 | @ OAK | 119 | L 2-6 | 64-55 | 4 | 13,237 | Brandon Morrow | Dallas Braden | Dallas Braden | Brian Tallet | Michael Wuertz | 553 | 516 | 37 |
| 2010-08-18 | @ OAK | 120 | L 4-5 | 64-56 | 4 | 18,046 | Marc Rzepczynski | Gio Gonzalez | Brad Ziegler | Casey Janssen | | 557 | 521 | 36 |
| 2010-08-20 | @ BOS | 121 | W 16-2 | 64-57 | 4 | 37,726 | Brett Cecil | Jon Lester | Brett Cecil | Jon Lester | | 573 | 523 | 50 |
| 2010-08-21 | @ BOS | 122 | L 4-5 | 64-58 | 4 | 37,614 | Ricky Romero | Daisuke Matsuzaka | Jonathan Papelbon | Casey Janssen | | 577 | 528 | 49 |
| 2010-08-22 | @ BOS | 123 | L 0-5 | 64-59 | 4 | 37,506 | Shaun Marcum | Clay Buchholz | Clay Buchholz | Shaun Marcum | Felix Doubront | 577 | 533 | 44 |
| 2010-08-23 | vs NYA | 124 | W 3-2 | 65-59 | 4 | 29,198 | Brandon Morrow | Ivan Nova | Scott Downs | David Robertson | Kevin Gregg | 580 | 535 | 45 |
| 2010-08-24 | vs NYA | 125 | L 5-11 | 66-59 | 4 | 30,567 | Marc Rzepczynski | Dustin Moseley | Dustin Moseley | Marc Rzepczynski | | 585 | 546 | 39 |
| 2010-08-25 | vs NYA | 126 | W 6-3 | 67-59 | 5 | 31,449 | Brett Cecil | Phil Hughes | Brett Cecil | Phil Hughes | Kevin Gregg | 591 | 549 | 42 |
| 2010-08-26 | vs DET | 127 | L 1-7 | 67-60 | 4 | 16,088 | Ricky Romero | Max Scherzer | Max Scherzer | Ricky Romero | | 592 | 556 | 36 |
| 2010-08-27 | vs DET | 128 | W 3-2 | 68-60 | 4 | 20,298 | Shaun Marcum | Justin Verlander | Shawn Camp | Phil Coke | | 595 | 558 | 37 |
| 2010-08-28 | vs DET | 129 | W 5-4 | 69-60 | 4 | 27,119 | Brandon Morrow | Alfredo Figaro | Brandon Morrow | Alfredo Figaro | Kevin Gregg | 600 | 562 | 38 |
| 2010-08-29 | vs DET | 130 | L 4-10 | 70-60 | 4 | 26,624 | Marc Rzepczynski | Rick Porcello | Rick Porcello | Marc Rzepczynski | | 604 | 572 | 32 |
| 2010-08-30 | @ TBA | 131 | L 2-6 | 70-61 | 4 | 11,968 | Brett Cecil | Wade Davis | Wade Davis | Brett Cecil | | 606 | 578 | 28 |
| 2010-08-31 | @ TBA | 132 | W 13-5 | 70-62 | 4 | 12,972 | Ricky Romero | Jeff Niemann | Ricky Romero | Jeff Niemann | | 619 | 583 | 36 |
| 2010-09-01 | @ TBA | 133 | L 1-2 | 70-63 | 4 | 14,859 | Shaun Marcum | David Price | David Price | Shawn Camp | Rafael Soriano | 620 | 585 | 35 |
| 2010-09-03 | @ NYA | 134 | L 3-7 | 70-64 | 4 | 44,739 | Brandon Morrow | Ivan Nova | Kerry Wood | Brandon Morrow | | 623 | 592 | 31 |
| 2010-09-04 | @ NYA | 135 | L 5-7 | 70-65 | 5 | 47,478 | Marc Rzepczynski | Javier Vazquez | Joba Chamberlain | Jason Frasor | Mariano Rivera | 628 | 599 | 29 |
| 2010-09-05 | @ NYA | 136 | W 7-3 | 71-65 | 4 | 47,737 | Brett Cecil | Phil Hughes | Brett Cecil | Phil Hughes | | 635 | 602 | 33 |
| 2010-09-06 | vs TEX | 137 | W 7-2 | 72-65 | 4 | 17,559 | Ricky Romero | Tommy Hunter | Ricky Romero | Tommy Hunter | | 642 | 604 | 38 |
| 2010-09-07 | vs TEX | 138 | W 8-5 | 73-65 | 4 | 10,518 | Shaun Marcum | Scott Feldman | Shaun Marcum | Scott Feldman | Kevin Gregg | 650 | 609 | 41 |
| 2010-09-08 | vs TEX | 139 | L 1-8 | 73-66 | 4 | 10,616 | Marc Rzepczynski | Derek Holland | Derek Holland | Marc Rzepczynski | | 651 | 617 | 34 |
| 2010-09-09 | vs TEX | 140 | L 2-4 | 73-67 | 4 | 10,658 | Shawn Hill | Colby Lewis | Colby Lewis | Shawn Hill | Neftali Feliz | 653 | 621 | 32 |
| 2010-09-10 | vs TBA | 141 | L 8-9 | 73-68 | 4 | 14,305 | Brett Cecil | James Shields | Joaquin Benoit | Kevin Gregg | Rafael Soriano | 661 | 630 | 31 |
| 2010-09-11 | vs TBA | 142 | L 1-13 | 73-69 | 4 | 17,632 | Ricky Romero | Wade Davis | Wade Davis | Ricky Romero | | 662 | 643 | 19 |
| 2010-09-12 | vs TBA | 143 | W 5-4 | 74-69 | 4 | 14,658 | Shaun Marcum | Jeff Niemann | Kevin Gregg | Rafael Soriano | | 667 | 647 | 20 |
| 2010-09-13 | @ BAL | 144 | L 3-4 | 74-70 | 4 | 9,882 | Marc Rzepczynski | Brian Matusz | David Hernandez | Brian Tallet | | 670 | 651 | 19 |
| 2010-09-14 | @ BAL | 145 | L 3-11 | 75-70 | 4 | 16,589 | Shawn Hill | Jake Arrieta | Jake Arrieta | Shawn Hill | | 673 | 662 | 11 |
| 2010-09-15 | @ BAL | 146 | L 1-3 | 75-71 | 4 | 13,651 | Kyle Drabek | Brad Bergesen | Brad Bergesen | Kyle Drabek | | 674 | 665 | 9 |
| 2010-09-17 | @ BOS | 147 | W 11-9 | 75-72 | 4 | 37,679 | Brett Cecil | John Lackey | Brett Cecil | John Lackey | Kevin Gregg | 685 | 674 | 11 |
| 2010-09-18 | @ BOS | 148 | W 4-3 | 76-72 | 4 | 37,863 | Ricky Romero | Josh Beckett | Ricky Romero | Josh Beckett | Kevin Gregg | 689 | 677 | 12 |
| 2010-09-19 | @ BOS | 149 | L 0-6 | 76-73 | 4 | 37,234 | Shaun Marcum | Jon Lester | Jon Lester | Shaun Marcum | | 689 | 683 | 6 |
| 2010-09-21 | vs SEA | 150 | W 5-3 | 77-73 | 4 | 12,158 | Marc Rzepczynski | Lucas French | Marc Rzepczynski | Lucas French | Kevin Gregg | 694 | 686 | 8 |
| 2010-09-22 | vs SEA | 151 | L 3-6 | 77-74 | 4 | 12,302 | Kyle Drabek | David Pauley | David Pauley | Kyle Drabek | | 697 | 692 | 5 |
| 2010-09-23 | vs SEA | 152 | W 1-0 | 78-74 | 4 | 12,590 | Shawn Hill | Felix Hernandez | Shawn Hill | Felix Hernandez | Kevin Gregg | 698 | 692 | 6 |
| 2010-09-24 | vs BAL | 153 | W 6-4 | 79-74 | 4 | 13,412 | Brett Cecil | Chris Tillman | Brett Cecil | Chris Tillman | Jesse Carlson | 704 | 696 | 8 |
| 2010-09-25 | vs BAL | 154 | W 5-4 | 80-74 | 4 | 21,504 | Ricky Romero | Jeremy Guthrie | David Purcey | Mark Hendrickson | | 709 | 700 | 9 |
| 2010-09-26 | vs BAL | 155 | W 5-2 | 81-74 | 4 | 17,831 | Shaun Marcum | Rick Vanden Hurk | Shaun Marcum | Rick Vanden Hurk | Jason Frasor | 714 | 702 | 12 |
| 2010-09-27 | vs NYA | 156 | W 7-5 | 82-74 | 4 | 16,004 | Marc Rzepczynski | A.J. Burnett | Marc Rzepczynski | A.J. Burnett | Kevin Gregg | 721 | 707 | 14 |
| 2010-09-28 | vs NYA | 157 | L 1-6 | 82-75 | 4 | 18,193 | Kyle Drabek | CC Sabathia | CC Sabathia | Kyle Drabek | | 722 | 713 | 9 |
| 2010-09-29 | vs NYA | 158 | W 8-4 | 83-75 | 4 | 33,143 | Brett Cecil | Javier Vazquez | Brett Cecil | Javier Vazquez | | 730 | 717 | 13 |
| 2010-09-30 | @ MIN | 159 | W 13-2 | 83-76 | 4 | 39,477 | Shawn Hill | Francisco Liriano | Casey Janssen | Francisco Liriano | | 743 | 719 | 24 |
| 2010-10-01 | @ MIN | 160 | W 6-3 | 84-76 | 4 | 39,937 | Ricky Romero | Carl Pavano | Ricky Romero | Jesse Crain | Kevin Gregg | 749 | 722 | 27 |
| 2010-10-02 | @ MIN | 161 | L 4-5 | 84-77 | 6 | 40,235 | Shaun Marcum | Brian Duensing | Matt Capps | Kevin Gregg | | 753 | 727 | 26 |
| 2010-10-03 | @ MIN | 162 | W 2-1 | 85-77 | 4 | 40,664 | Marc Rzepczynski | Nick Blackburn | Marc Rzepczynski | Nick Blackburn | Shawn Camp | 755 | 728 | 27 |