| 2010-04-05 | vs CLE | 1 | W 6-0 | 1-0 | 1 | 38,935 | Mark Buehrle | Jake Westbrook | Mark Buehrle | Jake Westbrook | | 6 | 0 | 6 |
| 2010-04-07 | vs CLE | 2 | L 3-5 | 1-1 | 2 | 19,514 | Jake Peavy | Fausto Carmona | Fausto Carmona | Randy Williams | Chris Perez | 9 | 5 | 4 |
| 2010-04-08 | vs CLE | 3 | L 3-5 | 1-2 | 4 | 18,637 | Gavin Floyd | Justin Masterson | Jensen Lewis | J.J. Putz | Chris Perez | 12 | 10 | 2 |
| 2010-04-09 | vs MIN | 4 | L 3-4 | 1-3 | 5 | 21,416 | John Danks | Francisco Liriano | Brian Duensing | Tony Pena | Jon Rauch | 15 | 14 | 1 |
| 2010-04-10 | vs MIN | 5 | L 1-2 | 1-4 | 5 | 28,337 | Freddy Garcia | Scott Baker | Scott Baker | Freddy Garcia | Jon Rauch | 16 | 16 | 0 |
| 2010-04-11 | vs MIN | 6 | W 5-4 | 2-4 | 3 | 25,550 | Mark Buehrle | Nick Blackburn | Mark Buehrle | Nick Blackburn | Bobby Jenks | 21 | 20 | 1 |
| 2010-04-12 | @ TOR | 7 | W 8-7 | 3-4 | 3 | 46,321 | Jake Peavy | Brian Tallet | Matt Thornton | Jeremy Accardo | Bobby Jenks | 29 | 27 | 2 |
| 2010-04-13 | @ TOR | 8 | L 2-4 | 3-5 | 3 | 12,167 | Gavin Floyd | Ricky Romero | Ricky Romero | Gavin Floyd | Kevin Gregg | 31 | 31 | 0 |
| 2010-04-14 | @ TOR | 9 | W 11-1 | 4-5 | 3 | 10,610 | John Danks | Brandon Morrow | John Danks | Brandon Morrow | | 42 | 32 | 10 |
| 2010-04-15 | @ TOR | 10 | L 3-7 | 4-6 | 3 | 10,744 | Freddy Garcia | Dana Eveland | Dana Eveland | Freddy Garcia | | 45 | 39 | 6 |
| 2010-04-16 | @ CLE | 11 | L 2-6 | 4-7 | 5 | 10,421 | Mark Buehrle | Mitch Talbot | Mitch Talbot | Mark Buehrle | | 47 | 45 | 2 |
| 2010-04-17 | @ CLE | 12 | L 2-3 | 4-8 | 5 | 12,885 | Jake Peavy | Jake Westbrook | Jensen Lewis | Matt Thornton | Chris Perez | 49 | 48 | 1 |
| 2010-04-18 | @ CLE | 13 | L 4-7 | 4-9 | 5 | 10,564 | Gavin Floyd | Fausto Carmona | Fausto Carmona | Gavin Floyd | Chris Perez | 53 | 55 | -2 |
| 2010-04-20 | vs TBA | 14 | W 4-1 | 5-9 | 4 | 19,260 | John Danks | David Price | John Danks | David Price | Bobby Jenks | 57 | 56 | 1 |
| 2010-04-21 | vs TBA | 15 | L 0-12 | 5-10 | 4 | 17,023 | Mark Buehrle | Wade Davis | Wade Davis | Mark Buehrle | | 57 | 68 | -11 |
| 2010-04-22 | vs TBA | 16 | L 2-10 | 6-10 | 4 | 18,207 | Jake Peavy | James Shields | James Shields | Jake Peavy | | 59 | 78 | -19 |
| 2010-04-23 | vs SEA | 17 | W 7-6 | 7-10 | 4 | 24,653 | Gavin Floyd | Ryan Rowland-Smith | Matt Thornton | Mark Lowe | | 66 | 84 | -18 |
| 2010-04-24 | vs SEA | 18 | W 5-4 | 8-10 | 4 | 25,253 | Freddy Garcia | Doug Fister | Bobby Jenks | David Aardsma | | 71 | 88 | -17 |
| 2010-04-25 | vs SEA | 19 | W 3-2 | 9-10 | 3 | 28,274 | John Danks | Jason Vargas | John Danks | Brandon League | Bobby Jenks | 74 | 90 | -16 |
| 2010-04-27 | @ TEX | 20 | L 2-4 | 9-11 | 3 | 14,589 | Mark Buehrle | C.J. Wilson | C.J. Wilson | Mark Buehrle | Frank Francisco | 76 | 94 | -18 |
| 2010-04-28 | @ TEX | 21 | L 5-6 | 9-12 | 3 | 20,432 | Jake Peavy | Rich Harden | Rich Harden | Jake Peavy | Neftali Feliz | 81 | 100 | -19 |
| 2010-04-29 | @ TEX | 22 | W 7-5 | 10-12 | 3 | 17,778 | Gavin Floyd | Scott Feldman | Gavin Floyd | Darren O'Day | | 88 | 105 | -17 |
| 2010-04-30 | @ NYA | 23 | L 4-6 | 10-13 | 3 | 44,783 | Freddy Garcia | Andy Pettitte | Alfredo Aceves | Matt Thornton | Mariano Rivera | 92 | 111 | -19 |
| 2010-05-01 | @ NYA | 24 | W 7-6 | 11-13 | 3 | 45,265 | John Danks | Javier Vazquez | Scott Linebrink | David Robertson | Bobby Jenks | 99 | 117 | -18 |
| 2010-05-02 | @ NYA | 25 | L 3-12 | 12-13 | 3 | 45,303 | Mark Buehrle | Phil Hughes | Phil Hughes | Mark Buehrle | | 102 | 129 | -27 |
| 2010-05-03 | vs KCA | 26 | W 5-1 | 13-13 | 3 | 21,208 | Jake Peavy | Gil Meche | Jake Peavy | Gil Meche | | 107 | 130 | -23 |
| 2010-05-04 | vs KCA | 27 | L 2-7 | 13-14 | 3 | 17,517 | Gavin Floyd | Luke Hochevar | Luke Hochevar | Gavin Floyd | | 109 | 137 | -28 |
| 2010-05-05 | vs KCA | 28 | W 9-2 | 14-14 | 3 | 21,255 | Freddy Garcia | Brian Bannister | Freddy Garcia | Brian Bannister | | 118 | 139 | -21 |
| 2010-05-06 | vs TOR | 29 | L 0-2 | 14-15 | 3 | 20,106 | John Danks | Dana Eveland | Dana Eveland | John Danks | Kevin Gregg | 118 | 141 | -23 |
| 2010-05-07 | vs TOR | 30 | L 4-7 | 14-16 | 3 | 20,072 | Mark Buehrle | Shaun Marcum | Scott Downs | J.J. Putz | | 122 | 148 | -26 |
| 2010-05-08 | vs TOR | 31 | W 7-3 | 15-16 | 4 | 24,945 | Jake Peavy | Brett Cecil | Jake Peavy | Brett Cecil | | 129 | 151 | -22 |
| 2010-05-09 | vs TOR | 32 | L 7-9 | 15-17 | 3 | 23,850 | Gavin Floyd | Ricky Romero | Jason Frasor | Bobby Jenks | Kevin Gregg | 136 | 160 | -24 |
| 2010-05-11 | @ MIN | 33 | W 5-2 | 16-17 | 3 | 38,764 | Freddy Garcia | Kevin Slowey | Freddy Garcia | Kevin Slowey | Bobby Jenks | 141 | 162 | -21 |
| 2010-05-12 | @ MIN | 34 | L 2-3 | 16-18 | 4 | 38,895 | John Danks | Carl Pavano | Carl Pavano | John Danks | Jon Rauch | 143 | 165 | -22 |
| 2010-05-14 | @ KCA | 35 | L 1-6 | 16-19 | 3 | 27,816 | Mark Buehrle | Gil Meche | Dusty Hughes | Mark Buehrle | | 144 | 171 | -27 |
| 2010-05-15 | @ KCA | 36 | W 5-4 | 17-19 | 3 | 22,192 | Jake Peavy | Luke Hochevar | Jake Peavy | Luke Hochevar | Matt Thornton | 149 | 175 | -26 |
| 2010-05-16 | @ KCA | 37 | L 3-5 | 17-20 | 3 | 13,922 | Gavin Floyd | Brian Bannister | Brian Bannister | Gavin Floyd | Joakim Soria | 152 | 180 | -28 |
| 2010-05-18 | @ DET | 38 | W 6-2 | 18-20 | 3 | 28,155 | Freddy Garcia | Rick Porcello | Freddy Garcia | Rick Porcello | | 158 | 182 | -24 |
| 2010-05-19 | vs ANA | 39 | L 2-3 | 18-21 | 3 | 23,271 | John Danks | Joe Saunders | Joe Saunders | John Danks | Brian Fuentes | 160 | 185 | -25 |
| 2010-05-20 | vs ANA | 40 | L 5-6 | 18-22 | 3 | 23,515 | Jake Peavy | Ervin Santana | Ervin Santana | Jake Peavy | Brian Fuentes | 165 | 191 | -26 |
| 2010-05-21 | vs FLO | 41 | W 8-0 | 19-22 | 3 | 20,652 | Mark Buehrle | Ricky Nolasco | Mark Buehrle | Ricky Nolasco | | 173 | 191 | -18 |
| 2010-05-22 | vs FLO | 42 | W 4-1 | 20-22 | 3 | 28,462 | Gavin Floyd | Chris Volstad | Gavin Floyd | Chris Volstad | Bobby Jenks | 177 | 192 | -15 |
| 2010-05-23 | vs FLO | 43 | L 0-13 | 20-23 | 3 | 28,298 | Freddy Garcia | Josh Johnson | Josh Johnson | Freddy Garcia | | 177 | 205 | -28 |
| 2010-05-24 | @ CLE | 44 | W 7-2 | 21-23 | 3 | 10,166 | John Danks | Justin Masterson | John Danks | Justin Masterson | | 184 | 207 | -23 |
| 2010-05-25 | @ CLE | 45 | L 3-7 | 21-24 | 3 | 14,441 | Jake Peavy | Mitch Talbot | Mitch Talbot | Jake Peavy | | 187 | 214 | -27 |
| 2010-05-26 | @ CLE | 46 | W 5-4 | 22-24 | 3 | 18,109 | Mark Buehrle | Jake Westbrook | Tony Pena | Jake Westbrook | | 192 | 218 | -26 |
| 2010-05-27 | @ TBA | 47 | L 1-5 | 22-25 | 3 | 13,299 | Gavin Floyd | Jeff Niemann | Jeff Niemann | Gavin Floyd | | 193 | 223 | -30 |
| 2010-05-28 | @ TBA | 48 | W 4-2 | 23-25 | 3 | 20,650 | Freddy Garcia | David Price | Freddy Garcia | David Price | Matt Thornton | 197 | 225 | -28 |
| 2010-05-29 | @ TBA | 49 | L 5-8 | 23-26 | 3 | 33,558 | John Danks | Wade Davis | Wade Davis | John Danks | Rafael Soriano | 202 | 233 | -31 |
| 2010-05-30 | @ TBA | 50 | W 8-5 | 24-26 | 3 | 26,878 | Jake Peavy | James Shields | Jake Peavy | James Shields | | 210 | 238 | -28 |
| 2010-06-01 | vs TEX | 51 | L 6-9 | 24-27 | 3 | 20,075 | Mark Buehrle | Rich Harden | Rich Harden | Mark Buehrle | Neftali Feliz | 216 | 247 | -31 |
| 2010-06-02 | vs TEX | 52 | L 5-9 | 24-28 | 3 | 19,516 | Gavin Floyd | Scott Feldman | Scott Feldman | Gavin Floyd | | 221 | 256 | -35 |
| 2010-06-03 | vs TEX | 53 | W 4-3 | 25-28 | 3 | 20,003 | Freddy Garcia | Colby Lewis | Freddy Garcia | Colby Lewis | Bobby Jenks | 225 | 259 | -34 |
| 2010-06-04 | vs CLE | 54 | L 1-10 | 25-29 | 3 | 20,713 | John Danks | Justin Masterson | Justin Masterson | John Danks | | 226 | 269 | -43 |
| 2010-06-05 | vs CLE | 55 | L 1-3 | 25-30 | 3 | 30,864 | Jake Peavy | Mitch Talbot | Mitch Talbot | Jake Peavy | Kerry Wood | 227 | 272 | -45 |
| 2010-06-06 | vs CLE | 56 | W 8-7 | 26-30 | 3 | 27,577 | Mark Buehrle | Jake Westbrook | J.J. Putz | Tony Sipp | Bobby Jenks | 235 | 279 | -44 |
| 2010-06-08 | vs DET | 57 | L 2-7 | 26-31 | 3 | 20,776 | Gavin Floyd | Armando Galarraga | Brad Thomas | Matt Thornton | | 237 | 286 | -49 |
| 2010-06-09 | vs DET | 58 | W 15-3 | 26-32 | 3 | 21,959 | Freddy Garcia | Rick Porcello | Freddy Garcia | Rick Porcello | | 252 | 289 | -37 |
| 2010-06-10 | vs DET | 59 | W 3-0 | 27-32 | 3 | 26,004 | John Danks | Max Scherzer | John Danks | Max Scherzer | Bobby Jenks | 255 | 289 | -34 |
| 2010-06-11 | @ CHN | 60 | W 10-5 | 27-33 | 3 | 41,129 | Jake Peavy | Randy Wells | Jake Peavy | Randy Wells | | 265 | 294 | -29 |
| 2010-06-12 | @ CHN | 61 | W 2-1 | 28-33 | 3 | 40,397 | Mark Buehrle | Carlos Silva | Mark Buehrle | Carlos Silva | Bobby Jenks | 267 | 295 | -28 |
| 2010-06-13 | @ CHN | 62 | L 0-1 | 28-34 | 3 | 40,456 | Gavin Floyd | Ted Lilly | Ted Lilly | Gavin Floyd | Carlos Marmol | 267 | 296 | -29 |
| 2010-06-15 | @ PIT | 63 | W 6-4 | 29-34 | 3 | 12,693 | Freddy Garcia | Brad Lincoln | Freddy Garcia | Brad Lincoln | Bobby Jenks | 273 | 300 | -27 |
| 2010-06-16 | @ PIT | 64 | W 7-2 | 30-34 | 3 | 15,218 | John Danks | Zach Duke | John Danks | Zach Duke | | 280 | 302 | -22 |
| 2010-06-17 | @ PIT | 65 | W 5-4 | 31-34 | 3 | 23,170 | Mark Buehrle | Ross Ohlendorf | Mark Buehrle | Ross Ohlendorf | Bobby Jenks | 285 | 306 | -21 |
| 2010-06-18 | @ WAS | 66 | W 2-1 | 32-34 | 3 | 40,325 | Gavin Floyd | Stephen Strasburg | J.J. Putz | Drew Storen | Bobby Jenks | 287 | 307 | -20 |
| 2010-06-19 | @ WAS | 67 | W 1-0 | 33-34 | 3 | 36,487 | Jake Peavy | J.D. Martin | Jake Peavy | J.D. Martin | | 288 | 307 | -19 |
| 2010-06-20 | @ WAS | 68 | W 6-3 | 34-34 | 3 | 31,763 | Freddy Garcia | John Lannan | Freddy Garcia | John Lannan | J.J. Putz | 294 | 310 | -16 |
| 2010-06-22 | vs ATL | 69 | W 9-6 | 35-34 | 3 | 28,773 | John Danks | Tommy Hanson | John Danks | Tommy Hanson | Bobby Jenks | 303 | 316 | -13 |
| 2010-06-23 | vs ATL | 70 | W 4-2 | 36-34 | 3 | 27,561 | Mark Buehrle | Tim Hudson | Mark Buehrle | Tim Hudson | Bobby Jenks | 307 | 318 | -11 |
| 2010-06-24 | vs ATL | 71 | W 2-0 | 37-34 | 3 | 31,076 | Gavin Floyd | Derek Lowe | J.J. Putz | Takashi Saito | Bobby Jenks | 309 | 318 | -9 |
| 2010-06-25 | vs CHN | 72 | W 6-0 | 38-34 | 3 | 39,364 | Jake Peavy | Carlos Zambrano | Jake Peavy | Carlos Zambrano | | 315 | 318 | -3 |
| 2010-06-26 | vs CHN | 73 | W 3-2 | 39-34 | 3 | 39,479 | Freddy Garcia | Carlos Silva | J.J. Putz | Andrew Cashner | Matt Thornton | 318 | 320 | -2 |
| 2010-06-27 | vs CHN | 74 | L 6-8 | 39-35 | 3 | 39,682 | John Danks | Ryan Dempster | Ryan Dempster | John Danks | | 324 | 328 | -4 |
| 2010-06-28 | @ KCA | 75 | L 1-3 | 39-36 | 3 | 15,056 | Mark Buehrle | Anthony Lerew | Anthony Lerew | Mark Buehrle | Joakim Soria | 325 | 331 | -6 |
| 2010-06-29 | @ KCA | 76 | W 4-3 | 40-36 | 3 | 19,364 | Gavin Floyd | Brian Bannister | Gavin Floyd | Brian Bannister | J.J. Putz | 329 | 334 | -5 |
| 2010-06-30 | @ KCA | 77 | L 6-7 | 40-37 | 3 | 18,335 | Jake Peavy | Zack Greinke | Zack Greinke | Jake Peavy | Joakim Soria | 335 | 341 | -6 |
| 2010-07-02 | @ TEX | 78 | W 5-3 | 41-37 | 3 | 30,193 | Freddy Garcia | Colby Lewis | J.J. Putz | Neftali Feliz | Matt Thornton | 340 | 344 | -4 |
| 2010-07-03 | @ TEX | 79 | L 1-3 | 41-38 | 3 | 25,986 | John Danks | Tommy Hunter | Tommy Hunter | John Danks | Neftali Feliz | 341 | 347 | -6 |
| 2010-07-04 | @ TEX | 80 | W 5-3 | 42-38 | 2 | 45,020 | Mark Buehrle | Scott Feldman | Mark Buehrle | Scott Feldman | Matt Thornton | 346 | 350 | -4 |
| 2010-07-05 | vs ANA | 81 | W 9-2 | 43-38 | 2 | 38,092 | Gavin Floyd | Scott Kazmir | Gavin Floyd | Scott Kazmir | Sergio Santos | 355 | 352 | 3 |
| 2010-07-06 | vs ANA | 82 | W 4-1 | 44-38 | 2 | 21,889 | Jake Peavy | Jered Weaver | Tony Pena | Jered Weaver | Bobby Jenks | 359 | 353 | 6 |
| 2010-07-07 | vs ANA | 83 | W 5-2 | 45-38 | 2 | 21,135 | Freddy Garcia | Joe Saunders | Freddy Garcia | Joe Saunders | Bobby Jenks | 364 | 355 | 9 |
| 2010-07-08 | vs ANA | 84 | W 1-0 | 46-38 | 2 | 27,734 | John Danks | Ervin Santana | John Danks | Ervin Santana | | 365 | 355 | 10 |
| 2010-07-09 | vs KCA | 85 | W 8-2 | 47-38 | 2 | 25,572 | Mark Buehrle | Bruce Chen | Mark Buehrle | Bruce Chen | | 373 | 357 | 16 |
| 2010-07-10 | vs KCA | 86 | W 5-1 | 48-38 | 2 | 32,339 | Gavin Floyd | Brian Bannister | Gavin Floyd | Brian Bannister | | 378 | 358 | 20 |
| 2010-07-11 | vs KCA | 87 | W 15-5 | 48-39 | 2 | 29,040 | Daniel Hudson | Anthony Lerew | Tony Pena | Anthony Lerew | | 393 | 363 | 30 |
| 2010-07-15 | @ MIN | 88 | W 8-7 | 49-39 | 2 | 40,697 | John Danks | Kevin Slowey | John Danks | Alex Burnett | Bobby Jenks | 401 | 370 | 31 |
| 2010-07-16 | @ MIN | 89 | L 4-7 | 49-40 | 2 | 40,427 | Gavin Floyd | Francisco Liriano | Francisco Liriano | Gavin Floyd | Jesse Crain | 405 | 377 | 28 |
| 2010-07-17 | @ MIN | 90 | L 2-3 | 49-41 | 2 | 40,637 | Mark Buehrle | Carl Pavano | Carl Pavano | Mark Buehrle | | 407 | 380 | 27 |
| 2010-07-18 | @ MIN | 91 | L 6-7 | 49-42 | 1 | 40,336 | Freddy Garcia | Nick Blackburn | Brian Duensing | Bobby Jenks | | 413 | 387 | 26 |
| 2010-07-19 | @ SEA | 92 | W 6-1 | 50-42 | 1 | 21,749 | Daniel Hudson | David Pauley | Daniel Hudson | David Pauley | | 419 | 388 | 31 |
| 2010-07-20 | @ SEA | 93 | W 4-0 | 51-42 | 1 | 21,366 | John Danks | Doug Fister | John Danks | Doug Fister | | 423 | 388 | 35 |
| 2010-07-21 | @ SEA | 94 | L 1-2 | 51-43 | 1 | 21,529 | Gavin Floyd | Felix Hernandez | Brandon League | Bobby Jenks | | 424 | 390 | 34 |
| 2010-07-23 | @ OAK | 95 | W 5-1 | 52-43 | 1 | 15,103 | Mark Buehrle | Trevor Cahill | Mark Buehrle | Trevor Cahill | | 429 | 391 | 38 |
| 2010-07-24 | @ OAK | 96 | L 2-10 | 53-43 | 1 | 17,439 | Freddy Garcia | Vin Mazzaro | Vin Mazzaro | Freddy Garcia | | 431 | 401 | 30 |
| 2010-07-25 | @ OAK | 97 | L 4-6 | 53-44 | 1 | 17,148 | Daniel Hudson | Dallas Braden | Dallas Braden | Daniel Hudson | Michael Wuertz | 435 | 407 | 28 |
| 2010-07-26 | vs SEA | 98 | W 6-1 | 54-44 | 1 | 38,815 | John Danks | Felix Hernandez | John Danks | Felix Hernandez | | 441 | 408 | 33 |
| 2010-07-27 | vs SEA | 99 | W 11-0 | 55-44 | 1 | 26,080 | Gavin Floyd | Ryan Rowland-Smith | Gavin Floyd | Ryan Rowland-Smith | | 452 | 408 | 44 |
| 2010-07-28 | vs SEA | 100 | W 6-5 | 56-44 | 1 | 25,126 | Mark Buehrle | Jason Vargas | Matt Thornton | Jamey Wright | Bobby Jenks | 458 | 413 | 45 |
| 2010-07-29 | vs SEA | 101 | W 9-5 | 57-44 | 1 | 28,483 | Freddy Garcia | David Pauley | Freddy Garcia | David Pauley | | 467 | 418 | 49 |
| 2010-07-30 | vs OAK | 102 | W 6-1 | 58-44 | 1 | 29,431 | Lucas Harrell | Brett Anderson | Lucas Harrell | Brett Anderson | | 473 | 419 | 54 |
| 2010-07-31 | vs OAK | 103 | L 2-6 | 58-45 | 1 | 35,852 | John Danks | Dallas Braden | Dallas Braden | John Danks | | 475 | 425 | 50 |
| 2010-08-01 | vs OAK | 104 | W 4-1 | 59-45 | 1 | 32,118 | Gavin Floyd | Gio Gonzalez | Gavin Floyd | Gio Gonzalez | Bobby Jenks | 479 | 426 | 53 |
| 2010-08-03 | @ DET | 105 | W 12-2 | 59-47 | 2 | 26,141 | Mark Buehrle | Rick Porcello | Mark Buehrle | Rick Porcello | | 491 | 428 | 63 |
| 2010-08-03 | @ DET | 106 | L 1-7 | 59-47 | 2 | 24,826 | Carlos Torres | Jeremy Bonderman | Jeremy Bonderman | Carlos Torres | | 492 | 435 | 57 |
| 2010-08-04 | @ DET | 107 | W 4-1 | 60-47 | 1 | 31,770 | Edwin Jackson | Armando Galarraga | Edwin Jackson | Armando Galarraga | Bobby Jenks | 496 | 436 | 60 |
| 2010-08-05 | @ DET | 108 | W 6-4 | 61-47 | 1 | 34,156 | Freddy Garcia | Max Scherzer | Sergio Santos | Jose Valverde | | 502 | 440 | 62 |
| 2010-08-06 | @ BAL | 109 | L 1-2 | 61-48 | 1 | 19,687 | John Danks | Brad Bergesen | Alfredo Simon | Tony Pena | | 503 | 442 | 61 |
| 2010-08-07 | @ BAL | 110 | W 4-2 | 62-48 | 1 | 24,929 | Gavin Floyd | Kevin Millwood | Gavin Floyd | Jason Berken | J.J. Putz | 507 | 444 | 63 |
| 2010-08-08 | @ BAL | 111 | L 3-4 | 62-49 | 1 | 18,283 | Mark Buehrle | Jeremy Guthrie | Jeremy Guthrie | Mark Buehrle | Alfredo Simon | 510 | 448 | 62 |
| 2010-08-09 | @ BAL | 112 | L 2-3 | 62-50 | 1 | 14,135 | Edwin Jackson | Brian Matusz | Matt Albers | J.J. Putz | | 512 | 451 | 61 |
| 2010-08-10 | vs MIN | 113 | L 6-12 | 63-50 | 1 | 30,900 | Freddy Garcia | Scott Baker | Scott Baker | Freddy Garcia | | 518 | 463 | 55 |
| 2010-08-11 | vs MIN | 114 | W 6-1 | 64-50 | 1 | 32,033 | John Danks | Glen Perkins | John Danks | Glen Perkins | | 524 | 464 | 60 |
| 2010-08-12 | vs MIN | 115 | L 1-6 | 64-51 | 1 | 33,237 | Gavin Floyd | Francisco Liriano | Francisco Liriano | Gavin Floyd | | 525 | 470 | 55 |
| 2010-08-13 | vs DET | 116 | W 8-4 | 65-51 | 1 | 34,834 | Mark Buehrle | Jeremy Bonderman | Mark Buehrle | Jeremy Bonderman | | 533 | 474 | 59 |
| 2010-08-14 | vs DET | 117 | L 2-3 | 65-52 | 1 | 36,548 | Edwin Jackson | Rick Porcello | Phil Coke | J.J. Putz | | 535 | 477 | 58 |
| 2010-08-15 | vs DET | 118 | L 8-13 | 66-52 | 1 | 36,287 | Freddy Garcia | Armando Galarraga | Brad Thomas | J.J. Putz | | 543 | 490 | 53 |
| 2010-08-17 | @ MIN | 119 | L 6-7 | 66-53 | 1 | 40,714 | John Danks | Scott Baker | Ron Mahay | Matt Thornton | | 549 | 497 | 52 |
| 2010-08-18 | @ MIN | 120 | L 6-7 | 66-54 | 2 | 40,702 | Gavin Floyd | Francisco Liriano | Jeff Manship | Gavin Floyd | Matt Capps | 555 | 504 | 51 |
| 2010-08-19 | @ MIN | 121 | W 11-0 | 67-54 | 1 | 40,723 | Mark Buehrle | Carl Pavano | Mark Buehrle | Carl Pavano | | 566 | 504 | 62 |
| 2010-08-21 | @ KCA | 122 | L 5-6 | 67-55 | 3 | 0 | Freddy Garcia | Philip Humber | Jesse Chavez | Chris Sale | | 571 | 510 | 61 |
| 2010-08-21 | @ KCA | 123 | W 7-6 | 67-55 | 3 | 25,543 | Tony Pena | Bryan Bullington | J.J. Putz | Greg Holland | | 578 | 516 | 62 |
| 2010-08-22 | @ KCA | 124 | L 2-3 | 68-56 | 2 | 18,877 | John Danks | Zack Greinke | Sean O'Sullivan | Scott Linebrink | | 580 | 519 | 61 |
| 2010-08-24 | vs BAL | 125 | W 7-5 | 69-56 | 1 | 26,263 | Gavin Floyd | Jeremy Guthrie | Gavin Floyd | Jeremy Guthrie | Bobby Jenks | 587 | 524 | 63 |
| 2010-08-25 | vs BAL | 126 | L 2-4 | 69-57 | 1 | 23,733 | Mark Buehrle | Brian Matusz | Brian Matusz | Mark Buehrle | Koji Uehara | 589 | 528 | 61 |
| 2010-08-26 | vs BAL | 127 | W 8-0 | 70-57 | 1 | 23,898 | Edwin Jackson | Jake Arrieta | Edwin Jackson | Jake Arrieta | | 597 | 528 | 69 |
| 2010-08-27 | vs NYA | 128 | W 9-4 | 71-57 | 1 | 38,596 | Freddy Garcia | A.J. Burnett | Freddy Garcia | A.J. Burnett | | 606 | 532 | 74 |
| 2010-08-28 | vs NYA | 129 | L 9-12 | 72-57 | 1 | 38,811 | John Danks | CC Sabathia | CC Sabathia | John Danks | Mariano Rivera | 615 | 544 | 71 |
| 2010-08-29 | vs NYA | 130 | L 1-2 | 72-58 | 1 | 39,433 | Gavin Floyd | Ivan Nova | Ivan Nova | Gavin Floyd | Mariano Rivera | 616 | 546 | 70 |
| 2010-08-30 | @ CLE | 131 | W 10-6 | 72-59 | 1 | 10,663 | Mark Buehrle | Mitch Talbot | Scott Linebrink | Rafael Perez | | 626 | 552 | 74 |
| 2010-08-31 | @ CLE | 132 | W 4-3 | 73-59 | 1 | 12,006 | Edwin Jackson | Justin Masterson | Edwin Jackson | Joe Smith | Bobby Jenks | 630 | 555 | 75 |
| 2010-09-01 | @ CLE | 133 | W 6-4 | 74-59 | 1 | 12,563 | Freddy Garcia | Carlos Carrasco | Tony Pena | Justin Germano | Chris Sale | 636 | 559 | 77 |
| 2010-09-04 | @ BOS | 134 | W 3-1 | 75-59 | 2 | 37,411 | John Danks | Clay Buchholz | John Danks | Clay Buchholz | Bobby Jenks | 639 | 560 | 79 |
| 2010-09-04 | @ BOS | 135 | W 3-1 | 75-59 | 2 | 37,858 | Gavin Floyd | John Lackey | Gavin Floyd | John Lackey | Bobby Jenks | 642 | 561 | 81 |
| 2010-09-05 | @ BOS | 136 | W 7-5 | 77-59 | 1 | 37,570 | Mark Buehrle | Josh Beckett | Scott Linebrink | Jonathan Papelbon | Matt Thornton | 649 | 566 | 83 |
| 2010-09-06 | @ DET | 137 | W 5-4 | 78-59 | 1 | 32,924 | Edwin Jackson | Max Scherzer | Chris Sale | Jose Valverde | | 654 | 570 | 84 |
| 2010-09-07 | @ DET | 138 | L 1-9 | 78-60 | 1 | 24,905 | Freddy Garcia | Justin Verlander | Justin Verlander | Freddy Garcia | | 655 | 579 | 76 |
| 2010-09-08 | @ DET | 139 | L 1-5 | 78-61 | 2 | 25,995 | John Danks | Jeremy Bonderman | Jeremy Bonderman | John Danks | | 656 | 584 | 72 |
| 2010-09-09 | @ DET | 140 | L 3-6 | 78-62 | 2 | 29,995 | Gavin Floyd | Rick Porcello | Rick Porcello | Gavin Floyd | Ryan Perry | 659 | 590 | 69 |
| 2010-09-10 | vs KCA | 141 | W 4-3 | 79-62 | 1 | 27,009 | Mark Buehrle | Bruce Chen | J.J. Putz | Rob Tejeda | Chris Sale | 663 | 593 | 70 |
| 2010-09-11 | vs KCA | 142 | L 2-8 | 79-63 | 2 | 26,389 | Edwin Jackson | Kyle Davies | Kyle Davies | Edwin Jackson | | 665 | 601 | 64 |
| 2010-09-12 | vs KCA | 143 | W 12-6 | 79-64 | 2 | 23,756 | Lucas Harrell | Sean O'Sullivan | Sergio Santos | Philip Humber | | 677 | 607 | 70 |
| 2010-09-14 | vs MIN | 144 | L 3-9 | 79-65 | 2 | 29,223 | John Danks | Francisco Liriano | Francisco Liriano | John Danks | | 680 | 616 | 64 |
| 2010-09-15 | vs MIN | 145 | L 3-9 | 79-66 | 2 | 30,063 | Gavin Floyd | Brian Duensing | Brian Duensing | Gavin Floyd | | 683 | 625 | 58 |
| 2010-09-16 | vs MIN | 146 | L 5-8 | 79-67 | 2 | 27,180 | Mark Buehrle | Carl Pavano | Carl Pavano | Mark Buehrle | Matt Capps | 688 | 633 | 55 |
| 2010-09-17 | vs DET | 147 | L 2-9 | 79-68 | 2 | 28,563 | Edwin Jackson | Max Scherzer | Max Scherzer | Edwin Jackson | | 690 | 642 | 48 |
| 2010-09-18 | vs DET | 148 | L 3-6 | 79-69 | 2 | 27,828 | Lucas Harrell | Justin Verlander | Justin Verlander | Sergio Santos | | 693 | 648 | 45 |
| 2010-09-19 | vs DET | 149 | L 7-9 | 79-70 | 2 | 25,417 | John Danks | Jeremy Bonderman | Robbie Weinhart | Sergio Santos | Daniel Schlereth | 700 | 657 | 43 |
| 2010-09-20 | @ OAK | 150 | L 0-3 | 79-71 | 2 | 10,090 | Gavin Floyd | Gio Gonzalez | Boof Bonser | Scott Linebrink | Craig Breslow | 700 | 660 | 40 |
| 2010-09-21 | @ OAK | 151 | L 2-7 | 79-72 | 2 | 11,158 | Mark Buehrle | Trevor Cahill | Trevor Cahill | Mark Buehrle | | 702 | 667 | 35 |
| 2010-09-22 | @ OAK | 152 | W 4-3 | 80-72 | 2 | 16,056 | Edwin Jackson | Brett Anderson | Matt Thornton | Brad Ziegler | Chris Sale | 706 | 670 | 36 |
| 2010-09-24 | @ ANA | 153 | W 2-1 | 81-72 | 2 | 41,046 | Freddy Garcia | Joel Pineiro | Matt Thornton | Fernando Rodney | | 708 | 671 | 37 |
| 2010-09-25 | @ ANA | 154 | W 6-2 | 82-72 | 2 | 40,758 | John Danks | Scott Kazmir | John Danks | Scott Kazmir | | 714 | 673 | 41 |
| 2010-09-26 | @ ANA | 155 | W 4-3 | 83-72 | 2 | 42,686 | Tony Pena | Jered Weaver | Tony Pena | Jered Weaver | Matt Thornton | 718 | 676 | 42 |
| 2010-09-27 | vs BOS | 156 | L 1-6 | 83-73 | 2 | 19,750 | Mark Buehrle | Clay Buchholz | Clay Buchholz | Mark Buehrle | | 719 | 682 | 37 |
| 2010-09-28 | vs BOS | 157 | W 5-4 | 84-73 | 2 | 16,982 | Edwin Jackson | John Lackey | Chris Sale | Michael Bowden | | 724 | 686 | 38 |
| 2010-09-29 | vs BOS | 158 | W 5-2 | 85-73 | 2 | 32,084 | Freddy Garcia | Josh Beckett | Freddy Garcia | Josh Beckett | Matt Thornton | 729 | 688 | 41 |
| 2010-09-30 | vs BOS | 159 | W 8-2 | 86-73 | 2 | 30,854 | John Danks | Jon Lester | John Danks | Jon Lester | | 737 | 690 | 47 |
| 2010-10-01 | vs CLE | 160 | L 3-7 | 86-74 | 2 | 23,128 | Tony Pena | Fausto Carmona | Fausto Carmona | Tony Pena | | 740 | 697 | 43 |
| 2010-10-02 | vs CLE | 161 | W 6-2 | 87-74 | 2 | 23,702 | Mark Buehrle | Carlos Carrasco | Mark Buehrle | Carlos Carrasco | | 746 | 699 | 47 |
| 2010-10-03 | vs CLE | 162 | W 6-5 | 88-74 | 2 | 24,539 | Edwin Jackson | Justin Germano | Edwin Jackson | Justin Germano | Chris Sale | 752 | 704 | 48 |