| 2008-03-31 | @ CLE | 1 | L 8-10 | 0-1 | 4 | 41,872 | Mark Buehrle | CC Sabathia | Rafael Betancourt | Octavio Dotel | Joe Borowski | 8 | 10 | -2 |
| 2008-04-02 | @ CLE | 2 | L 2-7 | 0-2 | 4 | 17,645 | Javier Vazquez | Fausto Carmona | Fausto Carmona | Javier Vazquez | | 10 | 17 | -7 |
| 2008-04-03 | @ CLE | 3 | W 2-1 | 1-2 | 3 | 15,785 | John Danks | Jake Westbrook | Octavio Dotel | Jake Westbrook | Bobby Jenks | 12 | 18 | -6 |
| 2008-04-04 | @ DET | 4 | W 8-5 | 2-2 | 2 | 34,569 | Jose Contreras | Nate Robertson | Boone Logan | Jason Grilli | Bobby Jenks | 20 | 23 | -3 |
| 2008-04-05 | @ DET | 5 | W 5-3 | 3-2 | 1 | 42,381 | Gavin Floyd | Dontrelle Willis | Gavin Floyd | Zach Miner | Bobby Jenks | 25 | 26 | -1 |
| 2008-04-06 | @ DET | 6 | W 13-2 | 4-2 | 1 | 35,230 | Mark Buehrle | Justin Verlander | Mark Buehrle | Justin Verlander | | 38 | 28 | 10 |
| 2008-04-07 | vs MIN | 7 | W 7-4 | 5-2 | 1 | 38,082 | Javier Vazquez | Nick Blackburn | Javier Vazquez | Matt Guerrier | Bobby Jenks | 45 | 32 | 13 |
| 2008-04-09 | vs MIN | 8 | L 5-12 | 5-3 | 2 | 16,499 | John Danks | Scott Baker | Scott Baker | John Danks | Brian Bass | 50 | 44 | 6 |
| 2008-04-11 | vs DET | 9 | L 2-5 | 5-4 | 2 | 26,094 | Jose Contreras | Dontrelle Willis | Aquilino Lopez | Jose Contreras | Todd Jones | 52 | 49 | 3 |
| 2008-04-12 | vs DET | 10 | W 7-0 | 6-4 | 1 | 29,649 | Gavin Floyd | Justin Verlander | Gavin Floyd | Justin Verlander | | 59 | 49 | 10 |
| 2008-04-13 | vs DET | 11 | W 11-0 | 7-4 | 1 | 26,294 | Javier Vazquez | Kenny Rogers | Javier Vazquez | Kenny Rogers | | 70 | 49 | 21 |
| 2008-04-14 | vs OAK | 12 | L 1-2 | 7-5 | 2 | 20,430 | Mark Buehrle | Greg Smith | Greg Smith | Mark Buehrle | Huston Street | 71 | 51 | 20 |
| 2008-04-15 | vs OAK | 13 | W 4-1 | 8-5 | 1 | 18,254 | John Danks | Dana Eveland | John Danks | Dana Eveland | Bobby Jenks | 75 | 52 | 23 |
| 2008-04-16 | @ BAL | 14 | W 3-1 | 9-5 | 1 | 12,080 | Jose Contreras | Adam Loewen | Jose Contreras | Adam Loewen | Bobby Jenks | 78 | 53 | 25 |
| 2008-04-17 | @ BAL | 15 | L 5-6 | 9-6 | 1 | 13,676 | Gavin Floyd | Jeremy Guthrie | George Sherrill | Boone Logan | | 83 | 59 | 24 |
| 2008-04-18 | @ TBA | 16 | W 9-2 | 10-6 | 1 | 12,379 | Javier Vazquez | Jeff Niemann | Javier Vazquez | Jeff Niemann | | 92 | 61 | 31 |
| 2008-04-19 | @ TBA | 17 | L 0-5 | 10-7 | 1 | 17,613 | Mark Buehrle | Andy Sonnanstine | Andy Sonnanstine | Mark Buehrle | | 92 | 66 | 26 |
| 2008-04-20 | @ TBA | 18 | W 6-0 | 11-7 | 1 | 17,212 | John Danks | Edwin Jackson | John Danks | Edwin Jackson | | 98 | 66 | 32 |
| 2008-04-22 | vs NYA | 19 | L 5-9 | 11-8 | 1 | 25,012 | Jose Contreras | Chien-Ming Wang | Chien-Ming Wang | Jose Contreras | | 103 | 75 | 28 |
| 2008-04-23 | vs NYA | 20 | L 4-6 | 11-9 | 1 | 27,751 | Javier Vazquez | Mike Mussina | Mike Mussina | Javier Vazquez | Mariano Rivera | 107 | 81 | 26 |
| 2008-04-24 | vs NYA | 21 | W 7-6 | 12-9 | 1 | 27,243 | Gavin Floyd | Phil Hughes | Bobby Jenks | Joba Chamberlain | | 114 | 87 | 27 |
| 2008-04-26 | vs BAL | 22 | L 1-5 | 13-10 | 1 | 23,043 | John Danks | Brian Burres | Brian Burres | John Danks | George Sherrill | 115 | 92 | 23 |
| 2008-04-26 | vs BAL | 23 | W 6-5 | 13-10 | 1 | 34,757 | Mark Buehrle | Steve Trachsel | Bobby Jenks | Randor Bierd | | 121 | 97 | 24 |
| 2008-04-27 | vs BAL | 24 | W 6-1 | 14-10 | 1 | 29,756 | Jose Contreras | Jeremy Guthrie | Jose Contreras | Jeremy Guthrie | | 127 | 98 | 29 |
| 2008-04-28 | vs BAL | 25 | L 3-4 | 14-11 | 1 | 17,367 | Javier Vazquez | Daniel Cabrera | Alberto Castillo | Horacio Ramirez | Rocky Cherry | 130 | 102 | 28 |
| 2008-04-29 | @ MIN | 26 | L 1-3 | 14-12 | 1 | 20,891 | Gavin Floyd | Boof Bonser | Boof Bonser | Gavin Floyd | Joe Nathan | 131 | 105 | 26 |
| 2008-04-30 | @ MIN | 27 | L 3-4 | 14-13 | 1 | 19,137 | Nick Masset | Nick Blackburn | Nick Blackburn | Ehren Wassermann | Joe Nathan | 134 | 109 | 25 |
| 2008-05-02 | @ TOR | 28 | L 0-2 | 14-14 | 1 | 21,057 | Mark Buehrle | Shaun Marcum | Shaun Marcum | Mark Buehrle | Scott Downs | 134 | 111 | 23 |
| 2008-05-03 | @ TOR | 29 | L 2-5 | 14-15 | 2 | 27,778 | John Danks | Jesse Litsch | Jesse Litsch | John Danks | B.J. Ryan | 136 | 116 | 20 |
| 2008-05-04 | @ TOR | 30 | L 3-4 | 14-16 | 2 | 26,247 | Jose Contreras | Roy Halladay | Roy Halladay | Jose Contreras | Scott Downs | 139 | 120 | 19 |
| 2008-05-05 | @ TOR | 31 | L 0-1 | 14-17 | 2 | 16,602 | Javier Vazquez | Dustin McGowan | Dustin McGowan | Javier Vazquez | B.J. Ryan | 139 | 121 | 18 |
| 2008-05-06 | vs MIN | 32 | W 7-1 | 15-17 | 2 | 23,480 | Gavin Floyd | Nick Blackburn | Gavin Floyd | Nick Blackburn | | 146 | 122 | 24 |
| 2008-05-07 | vs MIN | 33 | L 1-13 | 15-18 | 3 | 21,092 | Mark Buehrle | Livan Hernandez | Livan Hernandez | Mark Buehrle | | 147 | 135 | 12 |
| 2008-05-08 | vs MIN | 34 | W 6-2 | 16-18 | 2 | 25,193 | John Danks | Kevin Slowey | John Danks | Kevin Slowey | | 153 | 137 | 16 |
| 2008-05-09 | @ SEA | 35 | W 4-2 | 17-18 | 2 | 27,169 | Jose Contreras | Carlos Silva | Jose Contreras | Carlos Silva | Bobby Jenks | 157 | 139 | 18 |
| 2008-05-10 | @ SEA | 36 | W 8-4 | 18-18 | 2 | 33,078 | Javier Vazquez | Jarrod Washburn | Javier Vazquez | Jarrod Washburn | | 165 | 143 | 22 |
| 2008-05-11 | @ SEA | 37 | L 3-6 | 18-19 | 3 | 30,346 | Gavin Floyd | Miguel Batista | Miguel Batista | Gavin Floyd | J.J. Putz | 168 | 149 | 19 |
| 2008-05-12 | @ ANA | 38 | L 7-10 | 18-20 | 3 | 38,723 | Mark Buehrle | Nick Adenhart | Nick Adenhart | Mark Buehrle | Francisco Rodriguez | 175 | 159 | 16 |
| 2008-05-13 | @ ANA | 39 | L 0-2 | 18-21 | 3 | 35,333 | John Danks | Jered Weaver | Scot Shields | Octavio Dotel | Francisco Rodriguez | 175 | 161 | 14 |
| 2008-05-14 | @ ANA | 40 | W 6-1 | 19-21 | 3 | 37,059 | Jose Contreras | John Lackey | Jose Contreras | Scot Shields | | 181 | 162 | 19 |
| 2008-05-15 | @ ANA | 41 | W 4-3 | 20-21 | 3 | 41,444 | Javier Vazquez | Jon Garland | Octavio Dotel | Francisco Rodriguez | Bobby Jenks | 185 | 165 | 20 |
| 2008-05-16 | @ SFN | 42 | W 2-0 | 21-21 | 3 | 35,482 | Gavin Floyd | Jonathan Sanchez | Gavin Floyd | Jonathan Sanchez | Bobby Jenks | 187 | 165 | 22 |
| 2008-05-17 | @ SFN | 43 | W 3-1 | 22-21 | 1 | 37,006 | Mark Buehrle | Barry Zito | Mark Buehrle | Barry Zito | Bobby Jenks | 190 | 166 | 24 |
| 2008-05-18 | @ SFN | 44 | W 13-8 | 23-21 | 1 | 34,331 | John Danks | Matt Cain | Matt Thornton | Tyler Walker | Nick Masset | 203 | 174 | 29 |
| 2008-05-20 | vs CLE | 45 | W 4-1 | 24-21 | 1 | 27,533 | Jose Contreras | CC Sabathia | Jose Contreras | CC Sabathia | Bobby Jenks | 207 | 175 | 32 |
| 2008-05-21 | vs CLE | 46 | W 7-2 | 25-21 | 1 | 38,518 | Javier Vazquez | Paul Byrd | Javier Vazquez | Paul Byrd | | 214 | 177 | 37 |
| 2008-05-22 | vs CLE | 47 | W 3-1 | 26-21 | 1 | 28,040 | Mark Buehrle | Aaron Laffey | Scott Linebrink | Aaron Laffey | Bobby Jenks | 217 | 178 | 39 |
| 2008-05-23 | vs ANA | 48 | L 1-3 | 26-22 | 1 | 28,156 | Gavin Floyd | Joe Saunders | Joe Saunders | Gavin Floyd | Francisco Rodriguez | 218 | 181 | 37 |
| 2008-05-24 | vs ANA | 49 | L 0-2 | 26-23 | 1 | 38,434 | John Danks | Jered Weaver | Jered Weaver | John Danks | Francisco Rodriguez | 218 | 183 | 35 |
| 2008-05-25 | vs ANA | 50 | W 3-2 | 27-23 | 1 | 36,195 | Jose Contreras | John Lackey | Scott Linebrink | John Lackey | | 221 | 185 | 36 |
| 2008-05-26 | @ CLE | 51 | W 6-3 | 28-23 | 1 | 31,006 | Javier Vazquez | Paul Byrd | Boone Logan | Scott Elarton | Bobby Jenks | 227 | 188 | 39 |
| 2008-05-27 | @ CLE | 52 | L 2-8 | 28-24 | 1 | 25,426 | Mark Buehrle | Aaron Laffey | Aaron Laffey | Mark Buehrle | | 229 | 196 | 33 |
| 2008-05-28 | @ CLE | 53 | W 6-5 | 29-24 | 1 | 31,740 | Gavin Floyd | Jake Westbrook | Gavin Floyd | Rafael Betancourt | Bobby Jenks | 235 | 201 | 34 |
| 2008-05-29 | @ TBA | 54 | W 5-1 | 30-24 | 1 | 12,636 | John Danks | Edwin Jackson | John Danks | Edwin Jackson | | 240 | 202 | 38 |
| 2008-05-30 | @ TBA | 55 | L 1-2 | 30-25 | 1 | 14,679 | Jose Contreras | James Shields | Dan Wheeler | Scott Linebrink | | 241 | 204 | 37 |
| 2008-05-31 | @ TBA | 56 | L 0-2 | 30-26 | 1 | 36,048 | Javier Vazquez | Scott Kazmir | Scott Kazmir | Javier Vazquez | Grant Balfour | 241 | 206 | 35 |
| 2008-06-01 | @ TBA | 57 | L 3-4 | 30-27 | 1 | 24,720 | Mark Buehrle | Andy Sonnanstine | J.P. Howell | Matt Thornton | | 244 | 210 | 34 |
| 2008-06-03 | vs KCA | 58 | W 9-5 | 31-27 | 1 | 21,727 | Gavin Floyd | Zack Greinke | Gavin Floyd | Zack Greinke | | 253 | 215 | 38 |
| 2008-06-04 | vs KCA | 59 | W 6-4 | 32-27 | 1 | 23,515 | John Danks | Luke Hochevar | Octavio Dotel | Jimmy Gobble | | 259 | 219 | 40 |
| 2008-06-05 | vs KCA | 60 | W 6-2 | 33-27 | 1 | 25,104 | Jose Contreras | Gil Meche | Jose Contreras | Gil Meche | | 265 | 221 | 44 |
| 2008-06-06 | vs MIN | 61 | W 10-6 | 34-27 | 1 | 26,459 | Javier Vazquez | Nick Blackburn | Javier Vazquez | Nick Blackburn | | 275 | 227 | 48 |
| 2008-06-07 | vs MIN | 62 | W 11-2 | 35-27 | 1 | 32,930 | Mark Buehrle | Livan Hernandez | Mark Buehrle | Livan Hernandez | | 286 | 229 | 57 |
| 2008-06-08 | vs MIN | 63 | W 12-2 | 36-27 | 1 | 30,565 | Gavin Floyd | Kevin Slowey | Gavin Floyd | Kevin Slowey | | 298 | 231 | 67 |
| 2008-06-09 | vs MIN | 64 | W 7-5 | 37-27 | 1 | 21,126 | John Danks | Glen Perkins | Matt Thornton | Matt Guerrier | Bobby Jenks | 305 | 236 | 69 |
| 2008-06-10 | @ DET | 65 | L 4-6 | 37-28 | 1 | 38,295 | Jose Contreras | Nate Robertson | Nate Robertson | Jose Contreras | Todd Jones | 309 | 242 | 67 |
| 2008-06-11 | @ DET | 66 | L 1-5 | 37-29 | 1 | 38,693 | Javier Vazquez | Justin Verlander | Justin Verlander | Javier Vazquez | | 310 | 247 | 63 |
| 2008-06-12 | @ DET | 67 | L 1-2 | 37-30 | 1 | 40,297 | Mark Buehrle | Kenny Rogers | Todd Jones | Octavio Dotel | | 311 | 249 | 62 |
| 2008-06-13 | vs COL | 68 | W 5-4 | 38-30 | 1 | 30,143 | Gavin Floyd | Jeff Francis | Matt Thornton | Matt Herges | Bobby Jenks | 316 | 253 | 63 |
| 2008-06-14 | vs COL | 69 | L 0-2 | 38-31 | 1 | 35,663 | John Danks | Jorge de la Rosa | Jason Grilli | Octavio Dotel | Brian Fuentes | 316 | 255 | 61 |
| 2008-06-15 | vs COL | 70 | L 3-5 | 38-32 | 1 | 32,004 | Jose Contreras | Aaron Cook | Aaron Cook | Jose Contreras | Brian Fuentes | 319 | 260 | 59 |
| 2008-06-17 | vs PIT | 71 | W 16-5 | 39-32 | 1 | 28,012 | Javier Vazquez | Ian Snell | Javier Vazquez | Ian Snell | | 335 | 265 | 70 |
| 2008-06-18 | vs PIT | 72 | W 8-2 | 40-32 | 1 | 28,570 | Mark Buehrle | Tom Gorzelanny | Mark Buehrle | Tom Gorzelanny | | 343 | 267 | 76 |
| 2008-06-19 | vs PIT | 73 | W 13-8 | 41-32 | 1 | 26,685 | Gavin Floyd | Phil Dumatrait | Gavin Floyd | Phil Dumatrait | | 356 | 275 | 81 |
| 2008-06-20 | @ CHN | 74 | L 3-4 | 41-33 | 1 | 41,106 | John Danks | Ted Lilly | Kerry Wood | Scott Linebrink | | 359 | 279 | 80 |
| 2008-06-21 | @ CHN | 75 | L 7-11 | 41-34 | 1 | 41,021 | Jose Contreras | Jason Marquis | Jason Marquis | Jose Contreras | Kerry Wood | 366 | 290 | 76 |
| 2008-06-22 | @ CHN | 76 | L 1-7 | 41-35 | 1 | 41,034 | Javier Vazquez | Ryan Dempster | Ryan Dempster | Javier Vazquez | | 367 | 297 | 70 |
| 2008-06-24 | @ LAN | 77 | W 6-1 | 42-35 | 1 | 43,900 | Mark Buehrle | Derek Lowe | Mark Buehrle | Derek Lowe | | 373 | 298 | 75 |
| 2008-06-25 | @ LAN | 78 | L 0-5 | 42-36 | 1 | 40,162 | Gavin Floyd | Eric Stults | Eric Stults | Gavin Floyd | | 373 | 303 | 70 |
| 2008-06-26 | @ LAN | 79 | W 2-0 | 43-36 | 1 | 37,956 | John Danks | Clayton Kershaw | John Danks | Clayton Kershaw | Bobby Jenks | 375 | 303 | 72 |
| 2008-06-27 | vs CHN | 80 | W 10-3 | 44-36 | 1 | 39,132 | Jose Contreras | Ryan Dempster | Jose Contreras | Ryan Dempster | | 385 | 306 | 79 |
| 2008-06-28 | vs CHN | 81 | W 6-5 | 45-36 | 1 | 39,143 | Javier Vazquez | Sean Gallagher | Matt Thornton | Carlos Marmol | Bobby Jenks | 391 | 311 | 80 |
| 2008-06-29 | vs CHN | 82 | W 5-1 | 46-36 | 1 | 39,573 | Mark Buehrle | Sean Marshall | Mark Buehrle | Sean Marshall | | 396 | 312 | 84 |
| 2008-06-30 | vs CLE | 83 | W 9-7 | 47-36 | 1 | 38,466 | Gavin Floyd | Jeremy Sowers | Gavin Floyd | Jeremy Sowers | Matt Thornton | 405 | 319 | 86 |
| 2008-07-01 | vs CLE | 84 | W 3-2 | 48-36 | 1 | 25,502 | John Danks | Cliff Lee | Adam Russell | Joe Borowski | | 408 | 321 | 87 |
| 2008-07-02 | vs CLE | 85 | W 6-5 | 49-36 | 1 | 23,522 | Jose Contreras | CC Sabathia | Adam Russell | Masahide Kobayashi | | 414 | 326 | 88 |
| 2008-07-03 | vs OAK | 86 | L 2-3 | 49-37 | 1 | 26,730 | Javier Vazquez | Justin Duchscherer | Justin Duchscherer | Javier Vazquez | Huston Street | 416 | 329 | 87 |
| 2008-07-04 | vs OAK | 87 | L 1-7 | 49-38 | 1 | 29,600 | Mark Buehrle | Joe Blanton | Joe Blanton | Mark Buehrle | | 417 | 336 | 81 |
| 2008-07-05 | vs OAK | 88 | W 6-1 | 50-38 | 1 | 35,586 | Gavin Floyd | Greg Smith | Gavin Floyd | Greg Smith | | 423 | 337 | 86 |
| 2008-07-06 | vs OAK | 89 | W 4-3 | 51-38 | 1 | 31,955 | John Danks | Rich Harden | John Danks | Rich Harden | Scott Linebrink | 427 | 340 | 87 |
| 2008-07-08 | @ KCA | 90 | W 8-7 | 52-38 | 1 | 13,614 | Jose Contreras | Kyle Davies | Nick Masset | Rob Tejeda | | 435 | 347 | 88 |
| 2008-07-09 | @ KCA | 91 | W 7-6 | 53-38 | 1 | 16,502 | Javier Vazquez | Brian Bannister | Adam Russell | Rob Tejeda | Octavio Dotel | 442 | 353 | 89 |
| 2008-07-10 | @ KCA | 92 | L 1-4 | 53-39 | 1 | 14,547 | Mark Buehrle | Zack Greinke | Ron Mahay | Mark Buehrle | Joakim Soria | 443 | 357 | 86 |
| 2008-07-11 | @ TEX | 93 | L 2-7 | 53-40 | 1 | 28,003 | Gavin Floyd | Luis Mendoza | Luis Mendoza | Gavin Floyd | Eddie Guardado | 445 | 364 | 81 |
| 2008-07-12 | @ TEX | 94 | W 9-7 | 54-40 | 1 | 39,209 | John Danks | Kevin Millwood | John Danks | Kevin Millwood | | 454 | 371 | 83 |
| 2008-07-13 | @ TEX | 95 | L 11-12 | 54-41 | 1 | 28,459 | Jose Contreras | Matt Harrison | Jamey Wright | Boone Logan | | 465 | 383 | 82 |
| 2008-07-18 | vs KCA | 96 | W 9-5 | 55-41 | 1 | 36,291 | Mark Buehrle | Zack Greinke | Mark Buehrle | Zack Greinke | | 474 | 388 | 86 |
| 2008-07-19 | vs KCA | 97 | L 1-9 | 55-42 | 1 | 36,566 | Gavin Floyd | Gil Meche | Gil Meche | Gavin Floyd | | 475 | 397 | 78 |
| 2008-07-20 | vs KCA | 98 | L 7-8 | 55-43 | 1 | 32,269 | John Danks | Brian Bannister | Ramon Ramirez | Matt Thornton | Joakim Soria | 482 | 405 | 77 |
| 2008-07-21 | vs TEX | 99 | L 1-6 | 55-44 | 1 | 39,547 | Javier Vazquez | Scott Feldman | Scott Feldman | Javier Vazquez | | 483 | 411 | 72 |
| 2008-07-22 | vs TEX | 100 | W 10-2 | 56-44 | 1 | 32,670 | Mark Buehrle | Luis Mendoza | Mark Buehrle | Luis Mendoza | | 493 | 413 | 80 |
| 2008-07-23 | vs TEX | 101 | W 10-8 | 57-44 | 1 | 35,353 | Clayton Richard | Kevin Millwood | Octavio Dotel | Eddie Guardado | Bobby Jenks | 503 | 421 | 82 |
| 2008-07-25 | @ DET | 102 | W 6-5 | 58-44 | 1 | 44,393 | Gavin Floyd | Nate Robertson | D.J. Carrasco | Todd Jones | Bobby Jenks | 509 | 426 | 83 |
| 2008-07-26 | @ DET | 103 | W 7-6 | 59-44 | 1 | 45,280 | John Danks | Justin Verlander | John Danks | Justin Verlander | Bobby Jenks | 516 | 432 | 84 |
| 2008-07-27 | @ DET | 104 | L 4-6 | 59-45 | 1 | 41,790 | Javier Vazquez | Zach Miner | Zach Miner | Javier Vazquez | | 520 | 438 | 82 |
| 2008-07-28 | @ MIN | 105 | L 0-7 | 59-46 | 1 | 30,126 | Mark Buehrle | Kevin Slowey | Kevin Slowey | Mark Buehrle | | 520 | 445 | 75 |
| 2008-07-29 | @ MIN | 106 | L 5-6 | 59-47 | 1 | 35,999 | Clayton Richard | Glen Perkins | Glen Perkins | Clayton Richard | Joe Nathan | 525 | 451 | 74 |
| 2008-07-30 | @ MIN | 107 | W 8-3 | 60-47 | 1 | 42,705 | Gavin Floyd | Livan Hernandez | Gavin Floyd | Livan Hernandez | | 533 | 454 | 79 |
| 2008-07-31 | @ MIN | 108 | L 6-10 | 60-48 | 1 | 31,493 | John Danks | Scott Baker | Jesse Crain | Matt Thornton | | 539 | 464 | 75 |
| 2008-08-01 | @ KCA | 109 | W 4-2 | 61-48 | 1 | 21,291 | Javier Vazquez | Luke Hochevar | Javier Vazquez | Luke Hochevar | Bobby Jenks | 543 | 466 | 77 |
| 2008-08-02 | @ KCA | 110 | L 7-9 | 61-49 | 1 | 21,866 | Mark Buehrle | Kyle Davies | Kyle Davies | Mark Buehrle | Joakim Soria | 550 | 475 | 75 |
| 2008-08-03 | @ KCA | 111 | L 3-14 | 61-50 | 2 | 15,268 | Clayton Richard | Zack Greinke | Zack Greinke | Clayton Richard | | 553 | 489 | 64 |
| 2008-08-05 | vs DET | 112 | W 10-8 | 62-50 | 1 | 35,371 | Gavin Floyd | Nate Robertson | Adam Russell | Joel Zumaya | | 563 | 497 | 66 |
| 2008-08-06 | vs DET | 113 | W 5-1 | 63-50 | 1 | 34,124 | John Danks | Justin Verlander | John Danks | Justin Verlander | | 568 | 498 | 70 |
| 2008-08-07 | vs DET | 114 | L 3-8 | 63-51 | 1 | 36,383 | Javier Vazquez | Zach Miner | Zach Miner | Javier Vazquez | Fernando Rodney | 571 | 506 | 65 |
| 2008-08-08 | vs BOS | 115 | W 5-3 | 64-51 | 1 | 38,621 | Mark Buehrle | Jon Lester | Mark Buehrle | Jon Lester | Bobby Jenks | 576 | 509 | 67 |
| 2008-08-09 | vs BOS | 116 | L 2-6 | 64-52 | 2 | 39,243 | Jose Contreras | Daisuke Matsuzaka | Daisuke Matsuzaka | Boone Logan | | 578 | 515 | 63 |
| 2008-08-10 | vs BOS | 117 | W 6-5 | 65-52 | 1 | 39,008 | Gavin Floyd | Clay Buchholz | Gavin Floyd | Clay Buchholz | Bobby Jenks | 584 | 520 | 64 |
| 2008-08-11 | vs BOS | 118 | L 1-5 | 65-53 | 2 | 32,634 | John Danks | Josh Beckett | Josh Beckett | John Danks | | 585 | 525 | 60 |
| 2008-08-12 | vs KCA | 119 | W 9-0 | 66-53 | 1 | 31,099 | Javier Vazquez | Brian Bannister | Javier Vazquez | Brian Bannister | | 594 | 525 | 69 |
| 2008-08-13 | vs KCA | 120 | W 4-0 | 67-53 | 1 | 37,838 | Mark Buehrle | Luke Hochevar | Mark Buehrle | Luke Hochevar | | 598 | 525 | 73 |
| 2008-08-14 | vs KCA | 121 | W 9-2 | 68-53 | 1 | 32,788 | Lance Broadway | Kyle Davies | Lance Broadway | Kyle Davies | | 607 | 527 | 80 |
| 2008-08-15 | @ OAK | 122 | L 4-6 | 68-54 | 2 | 19,405 | Gavin Floyd | Dallas Braden | Huston Street | Horacio Ramirez | | 611 | 533 | 78 |
| 2008-08-16 | @ OAK | 123 | W 2-1 | 69-54 | 2 | 22,206 | John Danks | Greg Smith | John Danks | Greg Smith | Bobby Jenks | 613 | 534 | 79 |
| 2008-08-17 | @ OAK | 124 | W 13-1 | 70-54 | 2 | 28,843 | Javier Vazquez | Gio Gonzalez | Javier Vazquez | Gio Gonzalez | | 626 | 535 | 91 |
| 2008-08-18 | vs SEA | 125 | W 13-5 | 71-54 | 1 | 39,002 | Mark Buehrle | Jarrod Washburn | Mark Buehrle | Jarrod Washburn | | 639 | 540 | 99 |
| 2008-08-19 | vs SEA | 126 | W 5-0 | 72-54 | 1 | 26,414 | Clayton Richard | Felix Hernandez | Clayton Richard | Felix Hernandez | | 644 | 540 | 104 |
| 2008-08-20 | vs SEA | 127 | W 15-3 | 73-54 | 1 | 27,000 | Gavin Floyd | R.A. Dickey | Gavin Floyd | R.A. Dickey | | 659 | 543 | 116 |
| 2008-08-22 | vs TBA | 128 | L 4-9 | 73-55 | 2 | 38,747 | John Danks | Edwin Jackson | Edwin Jackson | John Danks | | 663 | 552 | 111 |
| 2008-08-23 | vs TBA | 129 | L 3-5 | 73-56 | 2 | 36,482 | Javier Vazquez | Scott Kazmir | Grant Balfour | Javier Vazquez | Dan Wheeler | 666 | 557 | 109 |
| 2008-08-24 | vs TBA | 130 | W 6-5 | 74-56 | 1 | 38,562 | Mark Buehrle | Andy Sonnanstine | Bobby Jenks | Jason Hammel | | 672 | 562 | 110 |
| 2008-08-25 | @ BAL | 131 | W 4-3 | 75-56 | 1 | 20,707 | Clayton Richard | Chris Waters | Clayton Richard | Chris Waters | Bobby Jenks | 676 | 565 | 111 |
| 2008-08-26 | @ BAL | 132 | W 8-3 | 76-56 | 1 | 15,398 | Gavin Floyd | Brian Burres | Gavin Floyd | Brian Burres | | 684 | 568 | 116 |
| 2008-08-27 | @ BAL | 133 | L 3-11 | 76-57 | 1 | 15,736 | John Danks | Radhames Liz | Radhames Liz | John Danks | | 687 | 579 | 108 |
| 2008-08-29 | @ BOS | 134 | L 0-8 | 76-58 | 1 | 37,755 | Javier Vazquez | Daisuke Matsuzaka | Daisuke Matsuzaka | Javier Vazquez | | 687 | 587 | 100 |
| 2008-08-30 | @ BOS | 135 | L 2-8 | 76-59 | 1 | 37,751 | Mark Buehrle | Michael Bowden | Michael Bowden | Mark Buehrle | | 689 | 595 | 94 |
| 2008-08-31 | @ BOS | 136 | W 4-2 | 77-59 | 1 | 37,391 | Gavin Floyd | Tim Wakefield | Gavin Floyd | Tim Wakefield | Bobby Jenks | 693 | 597 | 96 |
| 2008-09-01 | @ CLE | 137 | L 0-5 | 77-60 | 1 | 23,317 | Clayton Richard | Cliff Lee | Cliff Lee | Clayton Richard | | 693 | 602 | 91 |
| 2008-09-02 | @ CLE | 138 | L 3-9 | 77-61 | 1 | 20,980 | John Danks | Fausto Carmona | Fausto Carmona | John Danks | | 696 | 611 | 85 |
| 2008-09-03 | @ CLE | 139 | W 4-2 | 78-61 | 1 | 20,328 | Javier Vazquez | Jeremy Sowers | Javier Vazquez | Jeremy Sowers | Bobby Jenks | 700 | 613 | 87 |
| 2008-09-05 | vs ANA | 140 | W 10-2 | 79-61 | 1 | 32,502 | Mark Buehrle | Dustin Moseley | Mark Buehrle | Dustin Moseley | | 710 | 615 | 95 |
| 2008-09-06 | vs ANA | 141 | W 7-6 | 80-61 | 1 | 31,046 | Gavin Floyd | John Lackey | Ehren Wassermann | Justin Speier | | 717 | 621 | 96 |
| 2008-09-07 | vs ANA | 142 | L 2-3 | 80-62 | 1 | 26,029 | John Danks | Joe Saunders | Joe Saunders | Horacio Ramirez | Francisco Rodriguez | 719 | 624 | 95 |
| 2008-09-09 | vs TOR | 143 | L 1-3 | 80-64 | 1 | 24,621 | Javier Vazquez | A.J. Burnett | A.J. Burnett | Javier Vazquez | B.J. Ryan | 720 | 627 | 93 |
| 2008-09-09 | vs TOR | 144 | L 2-8 | 80-64 | 1 | 28,505 | Clayton Richard | Jesse Litsch | Jesse Litsch | Clayton Richard | | 722 | 635 | 87 |
| 2008-09-10 | vs TOR | 145 | W 6-5 | 81-64 | 1 | 26,198 | Mark Buehrle | Roy Halladay | Mark Buehrle | Roy Halladay | | 728 | 640 | 88 |
| 2008-09-11 | vs TOR | 146 | L 4-6 | 81-65 | 1 | 27,170 | Gavin Floyd | Shaun Marcum | Shaun Marcum | Gavin Floyd | B.J. Ryan | 732 | 646 | 86 |
| 2008-09-14 | vs DET | 147 | W 4-2 | 83-65 | 1 | 0 | Javier Vazquez | Justin Verlander | Javier Vazquez | Justin Verlander | | 736 | 648 | 88 |
| 2008-09-14 | vs DET | 148 | W 11-7 | 83-65 | 1 | 28,238 | John Danks | Kenny Rogers | Matt Thornton | Bobby Seay | | 747 | 655 | 92 |
| 2008-09-15 | @ NYA | 149 | L 2-4 | 83-66 | 1 | 53,236 | Mark Buehrle | Alfredo Aceves | Phil Coke | Ehren Wassermann | Mariano Rivera | 749 | 659 | 90 |
| 2008-09-16 | @ NYA | 150 | W 6-2 | 84-66 | 1 | 52,558 | Gavin Floyd | Andy Pettitte | Gavin Floyd | Andy Pettitte | | 755 | 661 | 94 |
| 2008-09-17 | @ NYA | 151 | L 1-5 | 84-67 | 1 | 52,671 | Clayton Richard | Phil Hughes | Brian Bruney | Clayton Richard | | 756 | 666 | 90 |
| 2008-09-18 | @ NYA | 152 | L 2-9 | 84-68 | 1 | 53,152 | Javier Vazquez | Mike Mussina | Mike Mussina | Javier Vazquez | | 758 | 675 | 83 |
| 2008-09-19 | @ KCA | 153 | W 9-4 | 85-68 | 1 | 26,049 | Mark Buehrle | Brian Bannister | Mark Buehrle | Brian Bannister | | 767 | 679 | 88 |
| 2008-09-20 | @ KCA | 154 | L 2-5 | 85-69 | 1 | 23,754 | Gavin Floyd | Kyle Davies | Kyle Davies | Gavin Floyd | Joakim Soria | 769 | 684 | 85 |
| 2008-09-21 | @ KCA | 155 | W 3-0 | 86-69 | 1 | 16,920 | John Danks | Brandon Duckworth | John Danks | Brandon Duckworth | Bobby Jenks | 772 | 684 | 88 |
| 2008-09-23 | @ MIN | 156 | L 3-9 | 86-70 | 1 | 35,225 | Javier Vazquez | Scott Baker | Scott Baker | Javier Vazquez | | 775 | 693 | 82 |
| 2008-09-24 | @ MIN | 157 | L 2-3 | 86-71 | 1 | 42,126 | Mark Buehrle | Nick Blackburn | Nick Blackburn | Mark Buehrle | Joe Nathan | 777 | 696 | 81 |
| 2008-09-25 | @ MIN | 158 | L 6-7 | 86-72 | 2 | 43,601 | Gavin Floyd | Kevin Slowey | Joe Nathan | Bobby Jenks | | 783 | 703 | 80 |
| 2008-09-26 | vs CLE | 159 | L 8-11 | 86-73 | 2 | 36,494 | John Danks | Scott Lewis | Scott Lewis | John Danks | Jensen Lewis | 791 | 714 | 77 |
| 2008-09-27 | vs CLE | 160 | L 6-12 | 86-74 | 2 | 36,031 | Javier Vazquez | Zach Jackson | Zach Jackson | Javier Vazquez | | 797 | 726 | 71 |
| 2008-09-28 | vs CLE | 161 | W 5-1 | 87-74 | 2 | 33,396 | Mark Buehrle | Bryan Bullington | Mark Buehrle | Bryan Bullington | | 802 | 727 | 75 |
| 2008-09-29 | vs DET | 162 | W 8-2 | 88-74 | 1 | 35,923 | Gavin Floyd | Freddy Garcia | Gavin Floyd | Armando Galarraga | | 810 | 729 | 81 |
| 2008-09-30 | vs MIN | 163 | W 1-0 | 89-74 | 1 | 40,354 | John Danks | Nick Blackburn | John Danks | Nick Blackburn | Bobby Jenks | 811 | 729 | 82 |