| 2008-03-31 | @ BAL | 1 | W 6-2 | 1-0 | 1 | 46,807 | James Shields | Jeremy Guthrie | James Shields | Jeremy Guthrie | | 6 | 2 | 4 |
| 2008-04-02 | @ BAL | 2 | L 6-9 | 1-1 | 4 | 10,505 | Matt Garza | Daniel Cabrera | Jamie Walker | Alberto Reyes | George Sherrill | 12 | 11 | 1 |
| 2008-04-04 | @ NYA | 3 | W 13-4 | 2-1 | 2 | 49,255 | Andy Sonnanstine | Ian Kennedy | Andy Sonnanstine | Ian Kennedy | | 25 | 15 | 10 |
| 2008-04-05 | @ NYA | 4 | W 6-3 | 3-1 | 2 | 52,247 | Edwin Jackson | Andy Pettitte | Edwin Jackson | Andy Pettitte | Troy Percival | 31 | 18 | 13 |
| 2008-04-06 | @ NYA | 5 | L 0-2 | 3-2 | 3 | 51,279 | James Shields | Chien-Ming Wang | Chien-Ming Wang | James Shields | Mariano Rivera | 31 | 20 | 11 |
| 2008-04-07 | @ NYA | 6 | L 1-6 | 3-3 | 4 | 41,302 | Jason Hammel | Mike Mussina | Mike Mussina | Jason Hammel | | 32 | 26 | 6 |
| 2008-04-08 | vs SEA | 7 | L 5-6 | 3-4 | 5 | 36,048 | Matt Garza | Erik Bedard | Erik Bedard | Gary Glover | Ryan Rowland-Smith | 37 | 32 | 5 |
| 2008-04-09 | vs SEA | 8 | L 1-7 | 3-5 | 5 | 12,106 | Andy Sonnanstine | Jarrod Washburn | Jarrod Washburn | Andy Sonnanstine | | 38 | 39 | -1 |
| 2008-04-10 | vs SEA | 9 | W 7-0 | 4-5 | 4 | 11,898 | Edwin Jackson | Miguel Batista | Edwin Jackson | Miguel Batista | | 45 | 39 | 6 |
| 2008-04-11 | vs BAL | 10 | W 10-5 | 5-5 | 3 | 12,146 | James Shields | Jeremy Guthrie | Alberto Reyes | Dennis Sarfate | | 55 | 44 | 11 |
| 2008-04-12 | vs BAL | 11 | L 2-3 | 5-6 | 5 | 19,295 | Jason Hammel | Daniel Cabrera | Chad Bradford | Dan Wheeler | George Sherrill | 57 | 47 | 10 |
| 2008-04-13 | vs BAL | 12 | W 6-2 | 6-6 | 4 | 16,748 | Jeff Niemann | Brian Burres | Jeff Niemann | Brian Burres | | 63 | 49 | 14 |
| 2008-04-14 | vs NYA | 13 | L 7-8 | 6-7 | 5 | 18,872 | Andy Sonnanstine | Ian Kennedy | Brian Bruney | Alberto Reyes | Mariano Rivera | 70 | 57 | 13 |
| 2008-04-15 | vs NYA | 14 | L 3-5 | 6-8 | 5 | 20,923 | Edwin Jackson | Andy Pettitte | Andy Pettitte | Edwin Jackson | Mariano Rivera | 73 | 62 | 11 |
| 2008-04-16 | @ MIN | 15 | L 5-6 | 6-9 | 5 | 20,209 | James Shields | Livan Hernandez | Juan Rincon | Dan Wheeler | Joe Nathan | 78 | 68 | 10 |
| 2008-04-17 | @ MIN | 16 | W 7-3 | 7-9 | 5 | 14,781 | Jason Hammel | Boof Bonser | Jason Hammel | Boof Bonser | J.P. Howell | 85 | 71 | 14 |
| 2008-04-18 | vs CHA | 17 | L 2-9 | 7-10 | 5 | 12,379 | Jeff Niemann | Javier Vazquez | Javier Vazquez | Jeff Niemann | | 87 | 80 | 7 |
| 2008-04-19 | vs CHA | 18 | W 5-0 | 8-10 | 5 | 17,613 | Andy Sonnanstine | Mark Buehrle | Andy Sonnanstine | Mark Buehrle | | 92 | 80 | 12 |
| 2008-04-20 | vs CHA | 19 | L 0-6 | 8-11 | 5 | 17,212 | Edwin Jackson | John Danks | John Danks | Edwin Jackson | | 92 | 86 | 6 |
| 2008-04-22 | vs TOR | 20 | W 6-4 | 9-11 | 5 | 8,269 | James Shields | Jesse Litsch | James Shields | Jesse Litsch | Troy Percival | 98 | 90 | 8 |
| 2008-04-23 | vs TOR | 21 | W 5-3 | 10-11 | 4 | 8,989 | Jason Hammel | Roy Halladay | Jason Hammel | Roy Halladay | Troy Percival | 103 | 93 | 10 |
| 2008-04-24 | vs TOR | 22 | W 5-3 | 11-11 | 4 | 9,540 | Andy Sonnanstine | Dustin McGowan | Andy Sonnanstine | Dustin McGowan | Troy Percival | 108 | 96 | 12 |
| 2008-04-25 | vs BOS | 23 | W 5-4 | 12-11 | 3 | 30,290 | Matt Garza | Tim Wakefield | Scott Dohmann | Mike Timlin | | 113 | 100 | 13 |
| 2008-04-26 | vs BOS | 24 | W 2-1 | 13-11 | 3 | 36,048 | Edwin Jackson | Clay Buchholz | Scott Dohmann | Clay Buchholz | Troy Percival | 115 | 101 | 14 |
| 2008-04-27 | vs BOS | 25 | W 3-0 | 14-11 | 2 | 32,363 | James Shields | Josh Beckett | James Shields | Josh Beckett | | 118 | 101 | 17 |
| 2008-04-29 | @ BAL | 26 | L 4-7 | 14-12 | 3 | 11,588 | Jason Hammel | Garrett Olson | Garrett Olson | Jason Hammel | George Sherrill | 122 | 108 | 14 |
| 2008-04-30 | @ BAL | 27 | W 8-1 | 15-12 | 3 | 11,944 | Andy Sonnanstine | Matt Albers | Andy Sonnanstine | Matt Albers | | 130 | 109 | 21 |
| 2008-05-01 | @ BAL | 28 | W 4-2 | 16-12 | 1 | 16,456 | Matt Garza | Brian Burres | Matt Garza | Brian Burres | Troy Percival | 134 | 111 | 23 |
| 2008-05-02 | @ BOS | 29 | L 3-7 | 16-13 | 3 | 37,541 | Edwin Jackson | Clay Buchholz | Clay Buchholz | Edwin Jackson | | 137 | 118 | 19 |
| 2008-05-03 | @ BOS | 30 | L 4-12 | 16-14 | 3 | 37,700 | James Shields | Josh Beckett | Josh Beckett | James Shields | | 141 | 130 | 11 |
| 2008-05-04 | @ BOS | 31 | L 3-7 | 16-15 | 3 | 37,091 | Scott Kazmir | Jon Lester | Jon Lester | Scott Kazmir | Jonathan Papelbon | 144 | 137 | 7 |
| 2008-05-06 | @ TOR | 32 | W 5-4 | 17-15 | 2 | 30,397 | Andy Sonnanstine | A.J. Burnett | Andy Sonnanstine | A.J. Burnett | Troy Percival | 149 | 141 | 8 |
| 2008-05-07 | @ TOR | 33 | L 2-6 | 17-16 | 2 | 19,276 | Matt Garza | Shaun Marcum | Shaun Marcum | Matt Garza | | 151 | 147 | 4 |
| 2008-05-08 | @ TOR | 34 | W 8-3 | 18-16 | 2 | 21,118 | Edwin Jackson | Jesse Litsch | J.P. Howell | Shawn Camp | | 159 | 150 | 9 |
| 2008-05-09 | vs ANA | 35 | W 2-0 | 19-16 | 2 | 12,039 | James Shields | Jon Garland | James Shields | Justin Speier | | 161 | 150 | 11 |
| 2008-05-10 | vs ANA | 36 | W 2-0 | 20-16 | 2 | 25,512 | Scott Kazmir | Joe Saunders | Scott Kazmir | Joe Saunders | Troy Percival | 163 | 150 | 13 |
| 2008-05-11 | vs ANA | 37 | W 8-5 | 21-16 | 2 | 13,010 | Andy Sonnanstine | Ervin Santana | J.P. Howell | Justin Speier | Troy Percival | 171 | 155 | 16 |
| 2008-05-12 | vs NYA | 38 | W 7-1 | 22-16 | 2 | 13,932 | Matt Garza | Andy Pettitte | Matt Garza | Andy Pettitte | | 178 | 156 | 22 |
| 2008-05-13 | vs NYA | 39 | W 2-1 | 23-16 | 1 | 16,558 | Edwin Jackson | Chien-Ming Wang | J.P. Howell | Mariano Rivera | | 180 | 157 | 23 |
| 2008-05-14 | vs NYA | 40 | L 1-2 | 23-17 | 1 | 20,936 | James Shields | Mike Mussina | Mike Mussina | James Shields | Mariano Rivera | 181 | 159 | 22 |
| 2008-05-15 | vs NYA | 41 | W 5-2 | 24-17 | 1 | 19,976 | Scott Kazmir | Ian Kennedy | Scott Kazmir | Ian Kennedy | Troy Percival | 186 | 161 | 25 |
| 2008-05-16 | @ SLN | 42 | W 3-1 | 25-17 | 1 | 43,136 | Andy Sonnanstine | Braden Looper | Andy Sonnanstine | Braden Looper | Troy Percival | 189 | 162 | 27 |
| 2008-05-17 | @ SLN | 43 | L 8-9 | 25-18 | 1 | 43,907 | Matt Garza | Adam Wainwright | Ryan Franklin | Dan Wheeler | | 197 | 171 | 26 |
| 2008-05-18 | @ SLN | 44 | L 4-5 | 25-19 | 2 | 46,392 | Edwin Jackson | Kyle Lohse | Chris Perez | Gary Glover | | 201 | 176 | 25 |
| 2008-05-19 | @ OAK | 45 | W 7-6 | 26-19 | 2 | 11,077 | James Shields | Joe Blanton | Jason Hammel | Chad Gaudin | Troy Percival | 208 | 182 | 26 |
| 2008-05-20 | @ OAK | 46 | W 3-2 | 27-19 | 2 | 11,272 | Scott Kazmir | Greg Smith | Scott Kazmir | Greg Smith | Troy Percival | 211 | 184 | 27 |
| 2008-05-21 | @ OAK | 47 | L 1-9 | 27-20 | 2 | 22,712 | Andy Sonnanstine | Dana Eveland | Dana Eveland | Andy Sonnanstine | | 212 | 193 | 19 |
| 2008-05-23 | vs BAL | 48 | W 2-0 | 28-20 | 2 | 13,635 | Matt Garza | Jeremy Guthrie | Matt Garza | Jeremy Guthrie | Troy Percival | 214 | 193 | 21 |
| 2008-05-24 | vs BAL | 49 | W 11-4 | 29-20 | 2 | 30,445 | Edwin Jackson | Steve Trachsel | Edwin Jackson | Steve Trachsel | | 225 | 197 | 28 |
| 2008-05-25 | vs BAL | 50 | W 5-4 | 30-20 | 1 | 17,762 | James Shields | Daniel Cabrera | Troy Percival | George Sherrill | | 230 | 201 | 29 |
| 2008-05-26 | vs TEX | 51 | W 7-3 | 31-20 | 1 | 12,174 | Scott Kazmir | Sidney Ponson | Scott Kazmir | Sidney Ponson | | 237 | 204 | 33 |
| 2008-05-27 | vs TEX | 52 | L 6-12 | 31-21 | 1 | 10,511 | Andy Sonnanstine | Vicente Padilla | Vicente Padilla | Andy Sonnanstine | | 243 | 216 | 27 |
| 2008-05-28 | vs TEX | 53 | W 5-3 | 32-21 | 1 | 10,927 | Matt Garza | Kason Gabbard | Matt Garza | Kason Gabbard | Dan Wheeler | 248 | 219 | 29 |
| 2008-05-29 | vs CHA | 54 | L 1-5 | 32-22 | 1 | 12,636 | Edwin Jackson | John Danks | John Danks | Edwin Jackson | | 249 | 224 | 25 |
| 2008-05-30 | vs CHA | 55 | W 2-1 | 33-22 | 1 | 14,679 | James Shields | Jose Contreras | Dan Wheeler | Scott Linebrink | | 251 | 225 | 26 |
| 2008-05-31 | vs CHA | 56 | W 2-0 | 34-22 | 1 | 36,048 | Scott Kazmir | Javier Vazquez | Scott Kazmir | Javier Vazquez | Grant Balfour | 253 | 225 | 28 |
| 2008-06-01 | vs CHA | 57 | W 4-3 | 35-22 | 1 | 24,720 | Andy Sonnanstine | Mark Buehrle | J.P. Howell | Matt Thornton | | 257 | 228 | 29 |
| 2008-06-03 | @ BOS | 58 | L 4-7 | 35-23 | 1 | 37,823 | Matt Garza | Justin Masterson | Justin Masterson | Matt Garza | Jonathan Papelbon | 261 | 235 | 26 |
| 2008-06-04 | @ BOS | 59 | L 1-5 | 35-24 | 2 | 37,474 | Edwin Jackson | Josh Beckett | Josh Beckett | Edwin Jackson | | 262 | 240 | 22 |
| 2008-06-05 | @ BOS | 60 | L 1-7 | 35-25 | 2 | 37,639 | James Shields | Jon Lester | Jon Lester | James Shields | | 263 | 247 | 16 |
| 2008-06-06 | @ TEX | 61 | W 12-4 | 36-25 | 2 | 21,783 | Scott Kazmir | Vicente Padilla | Scott Kazmir | Vicente Padilla | | 275 | 251 | 24 |
| 2008-06-07 | @ TEX | 62 | W 5-4 | 37-25 | 2 | 28,788 | Andy Sonnanstine | Scott Feldman | J.P. Howell | Joaquin Benoit | Dan Wheeler | 280 | 255 | 25 |
| 2008-06-08 | @ TEX | 63 | L 3-6 | 37-26 | 2 | 20,258 | Matt Garza | Doug Mathis | Doug Mathis | Matt Garza | | 283 | 261 | 22 |
| 2008-06-09 | @ ANA | 64 | W 13-4 | 38-26 | 2 | 42,019 | Edwin Jackson | Joe Saunders | Edwin Jackson | Joe Saunders | | 296 | 265 | 31 |
| 2008-06-10 | @ ANA | 65 | L 1-6 | 38-27 | 2 | 37,610 | James Shields | Jered Weaver | Jered Weaver | James Shields | | 297 | 271 | 26 |
| 2008-06-11 | @ ANA | 66 | L 2-4 | 38-28 | 2 | 36,622 | Scott Kazmir | John Lackey | John Lackey | Scott Kazmir | Francisco Rodriguez | 299 | 275 | 24 |
| 2008-06-13 | vs FLO | 67 | W 7-3 | 39-28 | 2 | 19,312 | Andy Sonnanstine | Ryan Tucker | Andy Sonnanstine | Ryan Tucker | | 306 | 278 | 28 |
| 2008-06-14 | vs FLO | 68 | W 4-1 | 40-28 | 2 | 31,195 | Matt Garza | Mark Hendrickson | Matt Garza | Mark Hendrickson | Troy Percival | 310 | 279 | 31 |
| 2008-06-15 | vs FLO | 69 | L 3-9 | 40-29 | 2 | 28,886 | Edwin Jackson | Ricky Nolasco | Ricky Nolasco | Edwin Jackson | | 313 | 288 | 25 |
| 2008-06-17 | vs CHN | 70 | W 3-2 | 41-29 | 2 | 31,607 | Scott Kazmir | Ryan Dempster | Grant Balfour | Neal Cotts | Troy Percival | 316 | 290 | 26 |
| 2008-06-18 | vs CHN | 71 | W 5-4 | 42-29 | 2 | 31,496 | Andy Sonnanstine | Carlos Zambrano | Andy Sonnanstine | Carlos Zambrano | Troy Percival | 321 | 294 | 27 |
| 2008-06-19 | vs CHN | 72 | W 8-3 | 43-29 | 2 | 34,441 | James Shields | Sean Gallagher | Grant Balfour | Carlos Marmol | | 329 | 297 | 32 |
| 2008-06-20 | vs HOU | 73 | L 3-4 | 43-30 | 2 | 14,741 | Matt Garza | Roy Oswalt | Roy Oswalt | Matt Garza | Jose Valverde | 332 | 301 | 31 |
| 2008-06-21 | vs HOU | 74 | W 4-3 | 44-30 | 2 | 29,953 | Edwin Jackson | Wandy Rodriguez | Dan Wheeler | Doug Brocail | | 336 | 304 | 32 |
| 2008-06-22 | vs HOU | 75 | L 2-3 | 44-31 | 2 | 19,778 | Scott Kazmir | Brandon Backe | Brandon Backe | Scott Kazmir | Jose Valverde | 338 | 307 | 31 |
| 2008-06-24 | @ FLO | 76 | W 6-4 | 45-31 | 2 | 12,352 | Andy Sonnanstine | Scott Olsen | J.P. Howell | Renyel Pinto | Troy Percival | 344 | 311 | 33 |
| 2008-06-25 | @ FLO | 77 | W 15-3 | 46-31 | 2 | 13,165 | James Shields | Ryan Tucker | James Shields | Ryan Tucker | | 359 | 314 | 45 |
| 2008-06-26 | @ FLO | 78 | W 6-1 | 47-31 | 2 | 17,107 | Matt Garza | Mark Hendrickson | Matt Garza | Mark Hendrickson | | 365 | 315 | 50 |
| 2008-06-27 | @ PIT | 79 | W 10-5 | 48-31 | 2 | 19,970 | Scott Kazmir | Jimmy Barthmaier | Scott Kazmir | Jimmy Barthmaier | | 375 | 320 | 55 |
| 2008-06-28 | @ PIT | 80 | L 3-4 | 48-32 | 2 | 17,970 | Edwin Jackson | Ty Taubenheim | John Van Benschoten | Jason Hammel | | 378 | 324 | 54 |
| 2008-06-29 | @ PIT | 81 | W 4-3 | 49-32 | 1 | 15,828 | Andy Sonnanstine | Tom Gorzelanny | Andy Sonnanstine | Tyler Yates | Troy Percival | 382 | 327 | 55 |
| 2008-06-30 | vs BOS | 82 | W 5-4 | 50-32 | 1 | 34,145 | James Shields | Justin Masterson | James Shields | Justin Masterson | J.P. Howell | 387 | 331 | 56 |
| 2008-07-01 | vs BOS | 83 | W 3-1 | 51-32 | 1 | 31,112 | Matt Garza | Tim Wakefield | Matt Garza | Tim Wakefield | Grant Balfour | 390 | 332 | 58 |
| 2008-07-02 | vs BOS | 84 | W 7-6 | 52-32 | 1 | 36,048 | Scott Kazmir | Daisuke Matsuzaka | Gary Glover | Craig Hansen | Dan Wheeler | 397 | 338 | 59 |
| 2008-07-04 | vs KCA | 85 | W 11-2 | 53-32 | 1 | 16,830 | Edwin Jackson | Brian Bannister | Edwin Jackson | Brian Bannister | | 408 | 340 | 68 |
| 2008-07-05 | vs KCA | 86 | W 3-0 | 54-32 | 1 | 30,418 | Andy Sonnanstine | Zack Greinke | Andy Sonnanstine | Zack Greinke | Grant Balfour | 411 | 340 | 71 |
| 2008-07-06 | vs KCA | 87 | W 9-2 | 55-32 | 1 | 20,587 | James Shields | Luke Hochevar | James Shields | Luke Hochevar | | 420 | 342 | 78 |
| 2008-07-07 | vs KCA | 88 | L 4-7 | 55-33 | 1 | 16,293 | Matt Garza | Gil Meche | Joakim Soria | Dan Wheeler | | 424 | 349 | 75 |
| 2008-07-08 | @ NYA | 89 | L 0-5 | 55-34 | 1 | 53,089 | Scott Kazmir | Andy Pettitte | Andy Pettitte | Scott Kazmir | | 424 | 354 | 70 |
| 2008-07-09 | @ NYA | 90 | L 1-2 | 55-35 | 1 | 53,552 | Edwin Jackson | Sidney Ponson | Mariano Rivera | Grant Balfour | | 425 | 356 | 69 |
| 2008-07-10 | @ CLE | 91 | L 2-13 | 55-36 | 1 | 22,665 | Andy Sonnanstine | Aaron Laffey | Aaron Laffey | Andy Sonnanstine | | 427 | 369 | 58 |
| 2008-07-11 | @ CLE | 92 | L 0-5 | 55-37 | 1 | 33,663 | James Shields | Cliff Lee | Cliff Lee | James Shields | | 427 | 374 | 53 |
| 2008-07-12 | @ CLE | 93 | L 4-8 | 55-38 | 1 | 35,706 | Matt Garza | Matt Ginter | Matt Ginter | Matt Garza | | 431 | 382 | 49 |
| 2008-07-13 | @ CLE | 94 | L 2-5 | 55-39 | 2 | 29,700 | Scott Kazmir | Jeremy Sowers | Tom Mastny | Scott Kazmir | Masahide Kobayashi | 433 | 387 | 46 |
| 2008-07-18 | vs TOR | 95 | W 2-1 | 56-39 | 1 | 23,706 | James Shields | A.J. Burnett | James Shields | A.J. Burnett | Grant Balfour | 435 | 388 | 47 |
| 2008-07-19 | vs TOR | 96 | W 6-4 | 57-39 | 1 | 32,669 | Matt Garza | Roy Halladay | Matt Garza | Roy Halladay | Dan Wheeler | 441 | 392 | 49 |
| 2008-07-20 | vs TOR | 97 | L 4-9 | 57-40 | 1 | 21,037 | Edwin Jackson | John Parrish | Shawn Camp | Edwin Jackson | | 445 | 401 | 44 |
| 2008-07-21 | vs OAK | 98 | W 4-0 | 58-40 | 1 | 12,428 | Scott Kazmir | Dana Eveland | Scott Kazmir | Dana Eveland | | 449 | 401 | 48 |
| 2008-07-22 | vs OAK | 99 | L 1-8 | 58-41 | 1 | 16,800 | Andy Sonnanstine | Dallas Braden | Dallas Braden | Andy Sonnanstine | | 450 | 409 | 41 |
| 2008-07-23 | vs OAK | 100 | W 4-3 | 59-41 | 1 | 23,437 | James Shields | Greg Smith | James Shields | Greg Smith | Troy Percival | 454 | 412 | 42 |
| 2008-07-24 | @ KCA | 101 | L 2-4 | 59-42 | 1 | 25,900 | Matt Garza | Gil Meche | Gil Meche | Matt Garza | Joakim Soria | 456 | 416 | 40 |
| 2008-07-25 | @ KCA | 102 | W 5-3 | 60-42 | 1 | 31,535 | Edwin Jackson | Brian Bannister | Edwin Jackson | Brian Bannister | Troy Percival | 461 | 419 | 42 |
| 2008-07-26 | @ KCA | 103 | W 5-3 | 61-42 | 1 | 24,322 | Scott Kazmir | Luke Hochevar | Alberto Reyes | Horacio Ramirez | Troy Percival | 466 | 422 | 44 |
| 2008-07-27 | @ KCA | 104 | L 1-6 | 61-43 | 1 | 13,779 | Andy Sonnanstine | Kyle Davies | Kyle Davies | Andy Sonnanstine | | 467 | 428 | 39 |
| 2008-07-28 | @ TOR | 105 | L 1-3 | 61-44 | 1 | 23,476 | James Shields | A.J. Burnett | A.J. Burnett | James Shields | B.J. Ryan | 468 | 431 | 37 |
| 2008-07-29 | @ TOR | 106 | W 3-0 | 62-44 | 1 | 26,791 | Matt Garza | Roy Halladay | Matt Garza | Roy Halladay | | 471 | 431 | 40 |
| 2008-07-30 | @ TOR | 107 | W 3-2 | 63-44 | 1 | 40,322 | Edwin Jackson | Scott Richmond | Edwin Jackson | Scott Richmond | Troy Percival | 474 | 433 | 41 |
| 2008-08-01 | vs DET | 108 | W 5-2 | 64-44 | 1 | 26,403 | Scott Kazmir | Zach Miner | Grant Balfour | Zach Miner | Troy Percival | 479 | 435 | 44 |
| 2008-08-02 | vs DET | 109 | W 9-3 | 65-44 | 1 | 36,048 | Andy Sonnanstine | Kenny Rogers | Andy Sonnanstine | Kenny Rogers | | 488 | 438 | 50 |
| 2008-08-03 | vs DET | 110 | W 6-5 | 66-44 | 1 | 33,438 | James Shields | Armando Galarraga | Trever Miller | Fernando Rodney | | 494 | 443 | 51 |
| 2008-08-04 | vs CLE | 111 | L 2-5 | 66-45 | 1 | 17,049 | Matt Garza | Cliff Lee | Cliff Lee | Matt Garza | Rafael Perez | 496 | 448 | 48 |
| 2008-08-05 | vs CLE | 112 | W 8-4 | 67-45 | 1 | 20,063 | Edwin Jackson | Fausto Carmona | Edwin Jackson | Fausto Carmona | | 504 | 452 | 52 |
| 2008-08-06 | vs CLE | 113 | W 10-7 | 68-45 | 1 | 27,533 | Scott Kazmir | Jeremy Sowers | Troy Percival | Masahide Kobayashi | | 514 | 459 | 55 |
| 2008-08-07 | @ SEA | 114 | L 1-2 | 68-46 | 1 | 25,423 | Andy Sonnanstine | Felix Hernandez | J.J. Putz | Dan Wheeler | | 515 | 461 | 54 |
| 2008-08-08 | @ SEA | 115 | W 5-3 | 69-46 | 1 | 30,220 | James Shields | Carlos Silva | James Shields | Carlos Silva | Troy Percival | 520 | 464 | 56 |
| 2008-08-09 | @ SEA | 116 | W 8-7 | 70-46 | 1 | 27,905 | Matt Garza | Ryan Rowland-Smith | Chad Bradford | Miguel Batista | Troy Percival | 528 | 471 | 57 |
| 2008-08-10 | @ SEA | 117 | W 11-3 | 71-46 | 1 | 30,336 | Edwin Jackson | R.A. Dickey | Edwin Jackson | R.A. Dickey | | 539 | 474 | 65 |
| 2008-08-12 | @ OAK | 118 | L 1-2 | 71-47 | 1 | 14,284 | Scott Kazmir | Gio Gonzalez | Gio Gonzalez | Scott Kazmir | Brad Ziegler | 540 | 476 | 64 |
| 2008-08-13 | @ OAK | 119 | W 3-2 | 72-47 | 1 | 21,438 | Andy Sonnanstine | Justin Duchscherer | Andy Sonnanstine | Justin Duchscherer | Troy Percival | 543 | 478 | 65 |
| 2008-08-14 | @ OAK | 120 | W 7-6 | 73-47 | 1 | 16,689 | James Shields | Sean Gallagher | Jason Hammel | Santiago Casilla | Trever Miller | 550 | 484 | 66 |
| 2008-08-15 | @ TEX | 121 | W 7-0 | 74-47 | 1 | 20,223 | Matt Garza | Kevin Millwood | Matt Garza | Kevin Millwood | | 557 | 484 | 73 |
| 2008-08-16 | @ TEX | 122 | L 0-3 | 74-48 | 1 | 29,238 | Edwin Jackson | Matt Harrison | Matt Harrison | Edwin Jackson | Eddie Guardado | 557 | 487 | 70 |
| 2008-08-17 | @ TEX | 123 | W 7-4 | 75-48 | 1 | 18,363 | Scott Kazmir | Dustin Nippert | Scott Kazmir | Dustin Nippert | Dan Wheeler | 564 | 491 | 73 |
| 2008-08-18 | vs ANA | 124 | W 6-4 | 76-48 | 1 | 15,896 | Andy Sonnanstine | Jon Garland | Andy Sonnanstine | Jon Garland | Dan Wheeler | 570 | 495 | 75 |
| 2008-08-19 | vs ANA | 125 | W 4-2 | 77-48 | 1 | 15,902 | James Shields | Ervin Santana | James Shields | Scot Shields | Dan Wheeler | 574 | 497 | 77 |
| 2008-08-20 | vs ANA | 126 | L 4-5 | 77-49 | 1 | 19,157 | Matt Garza | Jered Weaver | Jose Arredondo | Grant Balfour | Francisco Rodriguez | 578 | 502 | 76 |
| 2008-08-22 | @ CHA | 127 | W 9-4 | 78-49 | 1 | 38,747 | Edwin Jackson | John Danks | Edwin Jackson | John Danks | | 587 | 506 | 81 |
| 2008-08-23 | @ CHA | 128 | W 5-3 | 79-49 | 1 | 36,482 | Scott Kazmir | Javier Vazquez | Grant Balfour | Javier Vazquez | Dan Wheeler | 592 | 509 | 83 |
| 2008-08-24 | @ CHA | 129 | L 5-6 | 79-50 | 1 | 38,562 | Andy Sonnanstine | Mark Buehrle | Bobby Jenks | Jason Hammel | | 597 | 515 | 82 |
| 2008-08-26 | vs TOR | 130 | L 2-6 | 79-51 | 1 | 13,478 | James Shields | Roy Halladay | Roy Halladay | James Shields | | 599 | 521 | 78 |
| 2008-08-27 | vs TOR | 131 | W 1-0 | 80-51 | 1 | 12,678 | Matt Garza | David Purcey | Matt Garza | David Purcey | Dan Wheeler | 600 | 521 | 79 |
| 2008-08-28 | vs TOR | 132 | W 3-2 | 81-51 | 1 | 14,039 | Edwin Jackson | Jesse Litsch | Edwin Jackson | Jesse Litsch | Dan Wheeler | 603 | 523 | 80 |
| 2008-08-29 | vs BAL | 133 | W 14-3 | 82-51 | 1 | 21,439 | Scott Kazmir | Jeremy Guthrie | Scott Kazmir | Jeremy Guthrie | | 617 | 526 | 91 |
| 2008-08-30 | vs BAL | 134 | W 10-9 | 83-51 | 1 | 34,805 | Andy Sonnanstine | Chris Waters | Dan Wheeler | Rocky Cherry | | 627 | 535 | 92 |
| 2008-08-31 | vs BAL | 135 | W 10-4 | 84-51 | 1 | 32,379 | James Shields | Brian Burres | James Shields | Brian Burres | | 637 | 539 | 98 |
| 2008-09-02 | vs NYA | 136 | L 2-7 | 84-52 | 1 | 21,629 | Matt Garza | Mike Mussina | Mike Mussina | Matt Garza | | 639 | 546 | 93 |
| 2008-09-03 | vs NYA | 137 | L 4-8 | 84-53 | 1 | 25,215 | Edwin Jackson | Carl Pavano | Edwar Ramirez | Edwin Jackson | | 643 | 554 | 89 |
| 2008-09-04 | vs NYA | 138 | W 7-5 | 85-53 | 1 | 26,080 | Scott Kazmir | Darrell Rasner | Scott Kazmir | Darrell Rasner | Dan Wheeler | 650 | 559 | 91 |
| 2008-09-05 | @ TOR | 139 | L 4-6 | 85-54 | 1 | 32,477 | Andy Sonnanstine | Roy Halladay | Roy Halladay | Andy Sonnanstine | B.J. Ryan | 654 | 565 | 89 |
| 2008-09-06 | @ TOR | 140 | L 4-7 | 85-55 | 1 | 34,649 | James Shields | Shaun Marcum | Brian Tallet | Troy Percival | | 658 | 572 | 86 |
| 2008-09-07 | @ TOR | 141 | L 0-1 | 85-56 | 1 | 39,854 | Matt Garza | David Purcey | David Purcey | Matt Garza | Jesse Carlson | 658 | 573 | 85 |
| 2008-09-08 | @ BOS | 142 | L 0-3 | 85-57 | 1 | 37,662 | Edwin Jackson | Jon Lester | Jon Lester | Edwin Jackson | Jonathan Papelbon | 658 | 576 | 82 |
| 2008-09-09 | @ BOS | 143 | W 5-4 | 86-57 | 1 | 37,573 | Scott Kazmir | Daisuke Matsuzaka | Dan Wheeler | Jonathan Papelbon | Troy Percival | 663 | 580 | 83 |
| 2008-09-10 | @ BOS | 144 | W 4-2 | 87-57 | 1 | 38,114 | Andy Sonnanstine | Josh Beckett | Trever Miller | Mike Timlin | Jason Hammel | 667 | 582 | 85 |
| 2008-09-13 | @ NYA | 145 | W 7-1 | 88-58 | 1 | 54,088 | James Shields | Mike Mussina | James Shields | Mike Mussina | | 674 | 583 | 91 |
| 2008-09-13 | @ NYA | 146 | L 5-6 | 88-58 | 1 | 53,568 | Matt Garza | Sidney Ponson | Damaso Marte | J.P. Howell | Mariano Rivera | 679 | 589 | 90 |
| 2008-09-14 | @ NYA | 147 | L 4-8 | 88-59 | 1 | 54,279 | Edwin Jackson | Carl Pavano | Carl Pavano | Edwin Jackson | Mariano Rivera | 683 | 597 | 86 |
| 2008-09-15 | vs BOS | 148 | L 5-13 | 88-60 | 1 | 29,772 | Scott Kazmir | Daisuke Matsuzaka | Daisuke Matsuzaka | Scott Kazmir | | 688 | 610 | 78 |
| 2008-09-16 | vs BOS | 149 | W 2-1 | 89-60 | 1 | 32,079 | Andy Sonnanstine | Josh Beckett | Dan Wheeler | Justin Masterson | | 690 | 611 | 79 |
| 2008-09-17 | vs BOS | 150 | W 10-3 | 90-60 | 1 | 36,048 | Matt Garza | Tim Wakefield | Grant Balfour | Tim Wakefield | | 700 | 614 | 86 |
| 2008-09-18 | vs MIN | 151 | L 8-11 | 90-61 | 1 | 17,296 | James Shields | Glen Perkins | Eddie Guardado | Dan Wheeler | Joe Nathan | 708 | 625 | 83 |
| 2008-09-19 | vs MIN | 152 | W 11-1 | 91-61 | 1 | 28,306 | Edwin Jackson | Nick Blackburn | Edwin Jackson | Nick Blackburn | | 719 | 626 | 93 |
| 2008-09-20 | vs MIN | 153 | W 7-2 | 92-61 | 1 | 36,048 | Scott Kazmir | Kevin Slowey | Scott Kazmir | Kevin Slowey | | 726 | 628 | 98 |
| 2008-09-21 | vs MIN | 154 | L 1-4 | 92-62 | 1 | 36,048 | Andy Sonnanstine | Francisco Liriano | Francisco Liriano | Andy Sonnanstine | Joe Nathan | 727 | 632 | 95 |
| 2008-09-22 | @ BAL | 155 | W 4-2 | 93-62 | 1 | 12,489 | David Price | Brian Bass | Grant Balfour | Rocky Cherry | Dan Wheeler | 731 | 634 | 97 |
| 2008-09-23 | @ BAL | 156 | W 5-2 | 95-62 | 1 | 0 | James Shields | Garrett Olson | James Shields | Garrett Olson | Dan Wheeler | 736 | 636 | 100 |
| 2008-09-23 | @ BAL | 157 | W 7-5 | 95-62 | 1 | 15,215 | Mitch Talbot | Alfredo Simon | Jeff Niemann | Jamie Walker | J.P. Howell | 743 | 641 | 102 |
| 2008-09-24 | @ BAL | 158 | W 11-6 | 96-62 | 1 | 13,632 | Edwin Jackson | Radhames Liz | Edwin Jackson | Brian Burres | Trever Miller | 754 | 647 | 107 |
| 2008-09-25 | @ DET | 159 | L 5-7 | 96-63 | 1 | 36,259 | Scott Kazmir | Armando Galarraga | Armando Galarraga | Scott Kazmir | Fernando Rodney | 759 | 654 | 105 |
| 2008-09-26 | @ DET | 160 | L 4-6 | 96-64 | 1 | 39,617 | Andy Sonnanstine | Justin Verlander | Justin Verlander | Andy Sonnanstine | Fernando Rodney | 763 | 660 | 103 |
| 2008-09-27 | @ DET | 161 | L 3-4 | 96-65 | 1 | 40,756 | Matt Garza | Dontrelle Willis | Aquilino Lopez | Jeff Niemann | Fernando Rodney | 766 | 664 | 102 |
| 2008-09-28 | @ DET | 162 | W 8-7 | 97-65 | 1 | 40,373 | James Shields | Zach Miner | Edwin Jackson | Chris Lambert | Jason Hammel | 774 | 671 | 103 |