| 2008-03-31 | vs CHA | 1 | W 10-8 | 1-0 | 1 | 41,872 | CC Sabathia | Mark Buehrle | Rafael Betancourt | Octavio Dotel | Joe Borowski | 10 | 8 | 2 |
| 2008-04-02 | vs CHA | 2 | W 7-2 | 2-0 | 1 | 17,645 | Fausto Carmona | Javier Vazquez | Fausto Carmona | Javier Vazquez | | 17 | 10 | 7 |
| 2008-04-03 | vs CHA | 3 | L 1-2 | 2-1 | 2 | 15,785 | Jake Westbrook | John Danks | Octavio Dotel | Jake Westbrook | Bobby Jenks | 18 | 12 | 6 |
| 2008-04-04 | @ OAK | 4 | L 3-6 | 2-2 | 3 | 13,916 | Paul Byrd | Justin Duchscherer | Justin Duchscherer | Paul Byrd | | 21 | 18 | 3 |
| 2008-04-05 | @ OAK | 5 | L 1-6 | 2-3 | 4 | 16,279 | CC Sabathia | Dana Eveland | Dana Eveland | CC Sabathia | | 22 | 24 | -2 |
| 2008-04-06 | @ OAK | 6 | W 2-1 | 3-3 | 3 | 16,384 | Cliff Lee | Joe Blanton | Cliff Lee | Joe Blanton | Joe Borowski | 24 | 25 | -1 |
| 2008-04-07 | @ ANA | 7 | L 4-6 | 3-4 | 3 | 35,014 | Fausto Carmona | Joe Saunders | Scot Shields | Joe Borowski | | 28 | 31 | -3 |
| 2008-04-08 | @ ANA | 8 | W 4-3 | 4-4 | 3 | 37,587 | Jake Westbrook | Ervin Santana | Jake Westbrook | Justin Speier | | 32 | 34 | -2 |
| 2008-04-09 | @ ANA | 9 | L 5-9 | 4-5 | 3 | 36,168 | Paul Byrd | Dustin Moseley | Dustin Moseley | Paul Byrd | | 37 | 43 | -6 |
| 2008-04-11 | vs OAK | 10 | L 7-9 | 4-6 | 4 | 17,859 | CC Sabathia | Joe Blanton | Joe Blanton | CC Sabathia | Huston Street | 44 | 52 | -8 |
| 2008-04-12 | vs OAK | 11 | L 3-7 | 4-7 | 4 | 19,170 | Fausto Carmona | Lenny DiNardo | Lenny DiNardo | Fausto Carmona | | 47 | 59 | -12 |
| 2008-04-13 | vs OAK | 12 | W 7-1 | 5-7 | 4 | 17,228 | Cliff Lee | Chad Gaudin | Cliff Lee | Chad Gaudin | | 54 | 60 | -6 |
| 2008-04-14 | vs BOS | 13 | L 4-6 | 5-8 | 4 | 21,802 | Jake Westbrook | Jon Lester | Mike Timlin | Joe Borowski | Jonathan Papelbon | 58 | 66 | -8 |
| 2008-04-15 | vs BOS | 14 | L 3-5 | 5-9 | 4 | 25,135 | Paul Byrd | Tim Wakefield | David Aardsma | Jensen Lewis | Hideki Okajima | 61 | 71 | -10 |
| 2008-04-16 | vs DET | 15 | L 2-13 | 5-10 | 4 | 17,644 | CC Sabathia | Armando Galarraga | Armando Galarraga | CC Sabathia | | 63 | 84 | -21 |
| 2008-04-17 | vs DET | 16 | W 11-1 | 6-10 | 4 | 21,547 | Fausto Carmona | Justin Verlander | Fausto Carmona | Justin Verlander | | 74 | 85 | -11 |
| 2008-04-18 | @ MIN | 17 | W 4-0 | 7-10 | 3 | 22,366 | Cliff Lee | Francisco Liriano | Cliff Lee | Francisco Liriano | | 78 | 85 | -7 |
| 2008-04-19 | @ MIN | 18 | L 0-3 | 7-11 | 4 | 34,210 | Jake Westbrook | Nick Blackburn | Nick Blackburn | Jake Westbrook | Joe Nathan | 78 | 88 | -10 |
| 2008-04-20 | @ MIN | 19 | L 1-2 | 7-12 | 4 | 27,703 | Paul Byrd | Scott Baker | Matt Guerrier | Rafael Perez | | 79 | 90 | -11 |
| 2008-04-22 | @ KCA | 20 | W 15-1 | 8-12 | 4 | 16,165 | CC Sabathia | Gil Meche | CC Sabathia | Gil Meche | | 94 | 91 | 3 |
| 2008-04-24 | @ KCA | 21 | W 9-6 | 10-12 | 2 | 0 | Fausto Carmona | Brett Tomko | Fausto Carmona | Brett Tomko | Rafael Betancourt | 103 | 97 | 6 |
| 2008-04-24 | @ KCA | 22 | W 2-0 | 10-12 | 2 | 11,637 | Cliff Lee | Brian Bannister | Cliff Lee | Brian Bannister | | 105 | 97 | 8 |
| 2008-04-25 | vs NYA | 23 | W 6-4 | 11-12 | 2 | 31,467 | Paul Byrd | Andy Pettitte | Paul Byrd | Andy Pettitte | Rafael Betancourt | 111 | 101 | 10 |
| 2008-04-26 | vs NYA | 24 | W 4-3 | 12-12 | 2 | 35,765 | Jeremy Sowers | Ian Kennedy | Masahide Kobayashi | Ross Ohlendorf | | 115 | 104 | 11 |
| 2008-04-27 | vs NYA | 25 | L 0-1 | 12-13 | 2 | 31,598 | CC Sabathia | Chien-Ming Wang | Chien-Ming Wang | CC Sabathia | Mariano Rivera | 115 | 105 | 10 |
| 2008-04-28 | vs NYA | 26 | L 2-5 | 12-14 | 2 | 20,689 | Aaron Laffey | Mike Mussina | Mike Mussina | Aaron Laffey | Mariano Rivera | 117 | 110 | 7 |
| 2008-04-29 | vs SEA | 27 | L 2-7 | 12-15 | 4 | 13,827 | Fausto Carmona | Carlos Silva | Mark Lowe | Rafael Betancourt | | 119 | 117 | 2 |
| 2008-04-30 | vs SEA | 28 | W 8-3 | 13-15 | 3 | 15,279 | Cliff Lee | Jarrod Washburn | Cliff Lee | Jarrod Washburn | | 127 | 120 | 7 |
| 2008-05-01 | vs SEA | 29 | W 3-2 | 14-15 | 2 | 15,722 | Paul Byrd | Miguel Batista | Masahide Kobayashi | Mark Lowe | | 130 | 122 | 8 |
| 2008-05-03 | vs KCA | 30 | L 2-4 | 14-16 | 3 | 27,272 | CC Sabathia | Luke Hochevar | Luke Hochevar | CC Sabathia | Joakim Soria | 132 | 126 | 6 |
| 2008-05-04 | vs KCA | 31 | L 0-2 | 14-17 | 4 | 27,836 | Aaron Laffey | Gil Meche | Gil Meche | Aaron Laffey | Joakim Soria | 132 | 128 | 4 |
| 2008-05-06 | @ NYA | 32 | W 5-3 | 15-17 | 3 | 50,713 | Fausto Carmona | Andy Pettitte | Rafael Perez | Joba Chamberlain | Rafael Betancourt | 137 | 131 | 6 |
| 2008-05-07 | @ NYA | 33 | W 3-0 | 16-17 | 2 | 50,199 | Cliff Lee | Chien-Ming Wang | Cliff Lee | Chien-Ming Wang | Rafael Betancourt | 140 | 131 | 9 |
| 2008-05-08 | @ NYA | 34 | L 3-6 | 16-18 | 3 | 53,227 | Paul Byrd | Mike Mussina | Mike Mussina | Paul Byrd | Mariano Rivera | 143 | 137 | 6 |
| 2008-05-09 | vs TOR | 35 | W 6-1 | 17-18 | 3 | 26,472 | CC Sabathia | Roy Halladay | CC Sabathia | Roy Halladay | | 149 | 138 | 11 |
| 2008-05-10 | vs TOR | 36 | W 12-0 | 18-18 | 3 | 38,141 | Aaron Laffey | Dustin McGowan | Aaron Laffey | Dustin McGowan | | 161 | 138 | 23 |
| 2008-05-12 | vs TOR | 37 | W 3-0 | 19-19 | 2 | 0 | Fausto Carmona | A.J. Burnett | Fausto Carmona | A.J. Burnett | | 164 | 138 | 26 |
| 2008-05-12 | vs TOR | 38 | L 0-3 | 19-19 | 2 | 16,045 | Cliff Lee | Shaun Marcum | B.J. Ryan | Rafael Betancourt | Scott Downs | 164 | 141 | 23 |
| 2008-05-13 | vs OAK | 39 | W 4-0 | 20-19 | 2 | 16,974 | Paul Byrd | Justin Duchscherer | Paul Byrd | Justin Duchscherer | Masahide Kobayashi | 168 | 141 | 27 |
| 2008-05-14 | vs OAK | 40 | W 2-0 | 21-19 | 1 | 18,188 | CC Sabathia | Joe Blanton | CC Sabathia | Joe Blanton | | 170 | 141 | 29 |
| 2008-05-15 | vs OAK | 41 | W 4-2 | 22-19 | 1 | 26,764 | Aaron Laffey | Greg Smith | Aaron Laffey | Greg Smith | Masahide Kobayashi | 174 | 143 | 31 |
| 2008-05-16 | @ CIN | 42 | L 3-4 | 22-20 | 1 | 33,433 | Jeremy Sowers | Johnny Cueto | David Weathers | Jensen Lewis | Francisco Cordero | 177 | 147 | 30 |
| 2008-05-17 | @ CIN | 43 | L 2-4 | 22-21 | 2 | 42,023 | Fausto Carmona | Aaron Harang | Bill Bray | Masahide Kobayashi | | 179 | 151 | 28 |
| 2008-05-18 | @ CIN | 44 | L 4-6 | 22-22 | 2 | 34,612 | Cliff Lee | Edinson Volquez | Edinson Volquez | Cliff Lee | Francisco Cordero | 183 | 157 | 26 |
| 2008-05-20 | @ CHA | 45 | L 1-4 | 22-23 | 3 | 27,533 | CC Sabathia | Jose Contreras | Jose Contreras | CC Sabathia | Bobby Jenks | 184 | 161 | 23 |
| 2008-05-21 | @ CHA | 46 | L 2-7 | 22-24 | 3 | 38,518 | Paul Byrd | Javier Vazquez | Javier Vazquez | Paul Byrd | | 186 | 168 | 18 |
| 2008-05-22 | @ CHA | 47 | L 1-3 | 22-25 | 3 | 28,040 | Aaron Laffey | Mark Buehrle | Scott Linebrink | Aaron Laffey | Bobby Jenks | 187 | 171 | 16 |
| 2008-05-23 | vs TEX | 48 | L 9-13 | 22-26 | 3 | 39,947 | Fausto Carmona | Kason Gabbard | Kameron Loe | Fausto Carmona | | 196 | 184 | 12 |
| 2008-05-24 | vs TEX | 49 | W 5-2 | 23-26 | 3 | 40,504 | Cliff Lee | Scott Feldman | Cliff Lee | Scott Feldman | Joe Borowski | 201 | 186 | 15 |
| 2008-05-25 | vs TEX | 50 | L 1-2 | 23-27 | 3 | 35,464 | CC Sabathia | Doug Mathis | Jamey Wright | Masahide Kobayashi | C.J. Wilson | 202 | 188 | 14 |
| 2008-05-26 | vs CHA | 51 | L 3-6 | 23-28 | 3 | 31,006 | Paul Byrd | Javier Vazquez | Boone Logan | Scott Elarton | Bobby Jenks | 205 | 194 | 11 |
| 2008-05-27 | vs CHA | 52 | W 8-2 | 24-28 | 3 | 25,426 | Aaron Laffey | Mark Buehrle | Aaron Laffey | Mark Buehrle | | 213 | 196 | 17 |
| 2008-05-28 | vs CHA | 53 | L 5-6 | 24-29 | 3 | 31,740 | Jake Westbrook | Gavin Floyd | Gavin Floyd | Rafael Betancourt | Bobby Jenks | 218 | 202 | 16 |
| 2008-05-30 | @ KCA | 54 | W 5-4 | 25-29 | 3 | 25,243 | Cliff Lee | Gil Meche | Cliff Lee | Brett Tomko | Joe Borowski | 223 | 206 | 17 |
| 2008-05-31 | @ KCA | 55 | L 2-4 | 25-30 | 3 | 23,923 | CC Sabathia | Kyle Davies | Kyle Davies | CC Sabathia | Joakim Soria | 225 | 210 | 15 |
| 2008-06-01 | @ KCA | 56 | L 1-6 | 25-31 | 3 | 22,345 | Paul Byrd | Brian Bannister | Brian Bannister | Paul Byrd | | 226 | 216 | 10 |
| 2008-06-02 | @ TEX | 57 | W 13-9 | 26-31 | 3 | 17,247 | Aaron Laffey | Doug Mathis | Masahide Kobayashi | Eddie Guardado | | 239 | 225 | 14 |
| 2008-06-03 | @ TEX | 58 | L 7-12 | 26-32 | 3 | 16,373 | Tom Mastny | A.J. Murray | Frank Francisco | Tom Mastny | | 246 | 237 | 9 |
| 2008-06-04 | @ TEX | 59 | W 15-9 | 27-32 | 3 | 19,676 | Cliff Lee | Sidney Ponson | Cliff Lee | Elizardo Ramirez | | 261 | 246 | 15 |
| 2008-06-05 | @ TEX | 60 | L 4-9 | 27-33 | 3 | 17,795 | CC Sabathia | Kevin Millwood | Kevin Millwood | CC Sabathia | | 265 | 255 | 10 |
| 2008-06-06 | @ DET | 61 | W 4-2 | 28-33 | 3 | 40,990 | Paul Byrd | Justin Verlander | Paul Byrd | Justin Verlander | Joe Borowski | 269 | 257 | 12 |
| 2008-06-07 | @ DET | 62 | L 4-8 | 28-34 | 3 | 42,193 | Aaron Laffey | Kenny Rogers | Zach Miner | Masahide Kobayashi | Todd Jones | 273 | 265 | 8 |
| 2008-06-08 | @ DET | 63 | L 2-5 | 28-35 | 3 | 39,941 | Jeremy Sowers | Armando Galarraga | Armando Galarraga | Jeremy Sowers | Todd Jones | 275 | 270 | 5 |
| 2008-06-09 | @ DET | 64 | W 8-2 | 29-35 | 3 | 38,440 | Cliff Lee | Dontrelle Willis | Cliff Lee | Dontrelle Willis | | 283 | 272 | 11 |
| 2008-06-10 | vs MIN | 65 | W 1-0 | 30-35 | 3 | 26,874 | CC Sabathia | Scott Baker | CC Sabathia | Scott Baker | | 284 | 272 | 12 |
| 2008-06-11 | vs MIN | 66 | L 5-8 | 30-36 | 3 | 18,742 | Paul Byrd | Nick Blackburn | Nick Blackburn | Paul Byrd | Joe Nathan | 289 | 280 | 9 |
| 2008-06-12 | vs MIN | 67 | W 12-2 | 31-36 | 3 | 21,716 | Aaron Laffey | Livan Hernandez | Aaron Laffey | Livan Hernandez | | 301 | 282 | 19 |
| 2008-06-13 | vs SDN | 68 | W 9-5 | 32-36 | 3 | 31,399 | Jeremy Sowers | Josh Banks | Rafael Betancourt | Cla Meredith | Masahide Kobayashi | 310 | 287 | 23 |
| 2008-06-14 | vs SDN | 69 | L 3-8 | 32-37 | 3 | 37,484 | Cliff Lee | Cha-Seung Baek | Heath Bell | Edward Mujica | | 313 | 295 | 18 |
| 2008-06-15 | vs SDN | 70 | W 7-3 | 33-37 | 3 | 33,017 | CC Sabathia | Greg Maddux | CC Sabathia | Greg Maddux | | 320 | 298 | 22 |
| 2008-06-17 | @ COL | 71 | L 2-10 | 33-38 | 3 | 28,146 | Paul Byrd | Greg Reynolds | Greg Reynolds | Paul Byrd | | 322 | 308 | 14 |
| 2008-06-18 | @ COL | 72 | L 2-4 | 33-39 | 4 | 28,339 | Aaron Laffey | Jeff Francis | Jeff Francis | Aaron Laffey | Brian Fuentes | 324 | 312 | 12 |
| 2008-06-19 | @ COL | 73 | L 3-6 | 33-40 | 4 | 33,174 | Jeremy Sowers | Jorge de la Rosa | Jorge de la Rosa | Jeremy Sowers | Brian Fuentes | 327 | 318 | 9 |
| 2008-06-20 | @ LAN | 74 | W 6-4 | 34-40 | 4 | 50,667 | Cliff Lee | Clayton Kershaw | Joe Borowski | Takashi Saito | Masahide Kobayashi | 333 | 322 | 11 |
| 2008-06-21 | @ LAN | 75 | W 7-2 | 35-40 | 4 | 45,036 | CC Sabathia | Chan Ho Park | Masahide Kobayashi | Cory Wade | | 340 | 324 | 16 |
| 2008-06-22 | @ LAN | 76 | L 3-4 | 35-41 | 4 | 39,993 | Paul Byrd | Chad Billingsley | Chad Billingsley | Paul Byrd | Takashi Saito | 343 | 328 | 15 |
| 2008-06-24 | vs SFN | 77 | L 2-3 | 35-42 | 4 | 29,024 | Aaron Laffey | Jonathan Sanchez | Jonathan Sanchez | Rafael Betancourt | Brian Wilson | 345 | 331 | 14 |
| 2008-06-25 | vs SFN | 78 | L 1-4 | 35-43 | 5 | 25,654 | Jeremy Sowers | Barry Zito | Barry Zito | Jeremy Sowers | Brian Wilson | 346 | 335 | 11 |
| 2008-06-26 | vs SFN | 79 | W 4-1 | 36-43 | 4 | 25,257 | Cliff Lee | Matt Cain | Cliff Lee | Matt Cain | Joe Borowski | 350 | 336 | 14 |
| 2008-06-27 | vs CIN | 80 | W 6-0 | 37-43 | 4 | 34,844 | CC Sabathia | Daryl Thompson | CC Sabathia | Daryl Thompson | | 356 | 336 | 20 |
| 2008-06-28 | vs CIN | 81 | L 0-5 | 37-44 | 4 | 39,506 | Paul Byrd | Johnny Cueto | Johnny Cueto | Paul Byrd | | 356 | 341 | 15 |
| 2008-06-29 | vs CIN | 82 | L 5-9 | 37-45 | 4 | 37,079 | Aaron Laffey | Bronson Arroyo | Bronson Arroyo | Aaron Laffey | | 361 | 350 | 11 |
| 2008-06-30 | @ CHA | 83 | L 7-9 | 37-46 | 5 | 38,466 | Jeremy Sowers | Gavin Floyd | Gavin Floyd | Jeremy Sowers | Matt Thornton | 368 | 359 | 9 |
| 2008-07-01 | @ CHA | 84 | L 2-3 | 37-47 | 5 | 25,502 | Cliff Lee | John Danks | Adam Russell | Joe Borowski | | 370 | 362 | 8 |
| 2008-07-02 | @ CHA | 85 | L 5-6 | 37-48 | 5 | 23,522 | CC Sabathia | Jose Contreras | Adam Russell | Masahide Kobayashi | | 375 | 368 | 7 |
| 2008-07-04 | @ MIN | 86 | L 3-12 | 37-49 | 5 | 22,634 | Paul Byrd | Livan Hernandez | Livan Hernandez | Paul Byrd | | 378 | 380 | -2 |
| 2008-07-05 | @ MIN | 87 | L 6-9 | 37-50 | 5 | 31,887 | Aaron Laffey | Kevin Slowey | Kevin Slowey | Tom Mastny | Joe Nathan | 384 | 389 | -5 |
| 2008-07-06 | @ MIN | 88 | L 3-4 | 37-51 | 5 | 30,258 | Cliff Lee | Glen Perkins | Glen Perkins | Cliff Lee | Joe Nathan | 387 | 393 | -6 |
| 2008-07-08 | @ DET | 89 | L 2-9 | 37-52 | 5 | 40,443 | Jeremy Sowers | Justin Verlander | Justin Verlander | Jeremy Sowers | | 389 | 402 | -13 |
| 2008-07-09 | @ DET | 90 | L 6-8 | 37-53 | 5 | 41,062 | Paul Byrd | Eddie Bonine | Todd Jones | Jensen Lewis | | 395 | 410 | -15 |
| 2008-07-10 | vs TBA | 91 | W 13-2 | 38-53 | 5 | 22,665 | Aaron Laffey | Andy Sonnanstine | Aaron Laffey | Andy Sonnanstine | | 408 | 412 | -4 |
| 2008-07-11 | vs TBA | 92 | W 5-0 | 39-53 | 5 | 33,663 | Cliff Lee | James Shields | Cliff Lee | James Shields | | 413 | 412 | 1 |
| 2008-07-12 | vs TBA | 93 | W 8-4 | 40-53 | 5 | 35,706 | Matt Ginter | Matt Garza | Matt Ginter | Matt Garza | | 421 | 416 | 5 |
| 2008-07-13 | vs TBA | 94 | W 5-2 | 41-53 | 5 | 29,700 | Jeremy Sowers | Scott Kazmir | Tom Mastny | Scott Kazmir | Masahide Kobayashi | 426 | 418 | 8 |
| 2008-07-18 | @ SEA | 95 | L 2-8 | 41-54 | 5 | 42,570 | Aaron Laffey | Felix Hernandez | Felix Hernandez | Aaron Laffey | | 428 | 426 | 2 |
| 2008-07-19 | @ SEA | 96 | W 9-6 | 42-54 | 5 | 37,869 | Jeremy Sowers | Miguel Batista | Jeremy Sowers | Miguel Batista | | 437 | 432 | 5 |
| 2008-07-20 | @ SEA | 97 | W 6-2 | 43-54 | 5 | 32,230 | Cliff Lee | Carlos Silva | Cliff Lee | Carlos Silva | | 443 | 434 | 9 |
| 2008-07-21 | @ ANA | 98 | W 5-2 | 44-54 | 5 | 43,037 | Paul Byrd | Ervin Santana | Paul Byrd | Ervin Santana | Masahide Kobayashi | 448 | 436 | 12 |
| 2008-07-22 | @ ANA | 99 | L 2-3 | 44-55 | 5 | 43,505 | Matt Ginter | Jered Weaver | Darren Oliver | Matt Ginter | Francisco Rodriguez | 450 | 439 | 11 |
| 2008-07-23 | @ ANA | 100 | L 11-14 | 44-56 | 5 | 42,187 | Aaron Laffey | John Lackey | John Lackey | Aaron Laffey | Francisco Rodriguez | 461 | 453 | 8 |
| 2008-07-25 | vs MIN | 101 | W 5-4 | 45-56 | 4 | 33,512 | Cliff Lee | Livan Hernandez | Cliff Lee | Livan Hernandez | Rafael Perez | 466 | 457 | 9 |
| 2008-07-26 | vs MIN | 102 | L 4-11 | 45-57 | 4 | 35,390 | Fausto Carmona | Scott Baker | Scott Baker | Fausto Carmona | | 470 | 468 | 2 |
| 2008-07-27 | vs MIN | 103 | L 2-4 | 45-58 | 5 | 31,562 | Jeremy Sowers | Nick Blackburn | Matt Guerrier | Rafael Perez | Joe Nathan | 472 | 472 | 0 |
| 2008-07-28 | vs DET | 104 | W 5-0 | 46-58 | 5 | 24,689 | Paul Byrd | Kenny Rogers | Paul Byrd | Kenny Rogers | | 477 | 472 | 5 |
| 2008-07-29 | vs DET | 105 | L 5-8 | 46-59 | 5 | 30,625 | Matt Ginter | Armando Galarraga | Armando Galarraga | Matt Ginter | | 482 | 480 | 2 |
| 2008-07-30 | vs DET | 106 | L 12-14 | 46-60 | 5 | 26,596 | Cliff Lee | Nate Robertson | Casey Fossum | Juan Rincon | | 494 | 494 | 0 |
| 2008-07-31 | vs DET | 107 | W 9-4 | 47-60 | 5 | 34,186 | Fausto Carmona | Justin Verlander | Fausto Carmona | Justin Verlander | | 503 | 498 | 5 |
| 2008-08-01 | @ MIN | 108 | L 1-4 | 47-61 | 5 | 33,709 | Jeremy Sowers | Nick Blackburn | Nick Blackburn | Jeremy Sowers | Joe Nathan | 504 | 502 | 2 |
| 2008-08-02 | @ MIN | 109 | W 5-1 | 48-61 | 5 | 40,937 | Paul Byrd | Kevin Slowey | Paul Byrd | Kevin Slowey | | 509 | 503 | 6 |
| 2008-08-03 | @ MIN | 110 | L 2-6 | 48-62 | 5 | 39,818 | Matt Ginter | Francisco Liriano | Francisco Liriano | Matt Ginter | | 511 | 509 | 2 |
| 2008-08-04 | @ TBA | 111 | W 5-2 | 49-62 | 5 | 17,049 | Cliff Lee | Matt Garza | Cliff Lee | Matt Garza | Rafael Perez | 516 | 511 | 5 |
| 2008-08-05 | @ TBA | 112 | L 4-8 | 49-63 | 5 | 20,063 | Fausto Carmona | Edwin Jackson | Edwin Jackson | Fausto Carmona | | 520 | 519 | 1 |
| 2008-08-06 | @ TBA | 113 | L 7-10 | 49-64 | 5 | 27,533 | Jeremy Sowers | Scott Kazmir | Troy Percival | Masahide Kobayashi | | 527 | 529 | -2 |
| 2008-08-08 | @ TOR | 114 | W 5-2 | 50-64 | 5 | 31,627 | Anthony Reyes | David Purcey | Anthony Reyes | David Purcey | Jensen Lewis | 532 | 531 | 1 |
| 2008-08-09 | @ TOR | 115 | W 4-2 | 51-64 | 5 | 39,623 | Paul Byrd | Roy Halladay | Paul Byrd | Roy Halladay | | 536 | 533 | 3 |
| 2008-08-10 | @ TOR | 116 | W 4-0 | 52-64 | 5 | 36,447 | Cliff Lee | Scott Richmond | Cliff Lee | Scott Richmond | | 540 | 533 | 7 |
| 2008-08-11 | vs BAL | 117 | W 13-8 | 53-64 | 5 | 23,408 | Fausto Carmona | Dennis Sarfate | Edward Mujica | Rocky Cherry | | 553 | 541 | 12 |
| 2008-08-12 | vs BAL | 118 | W 7-5 | 54-64 | 4 | 21,143 | Jeremy Sowers | Garrett Olson | Rafael Perez | Jim Johnson | Jensen Lewis | 560 | 546 | 14 |
| 2008-08-13 | vs BAL | 119 | L 1-6 | 54-65 | 4 | 21,299 | Anthony Reyes | Jeremy Guthrie | Jeremy Guthrie | Anthony Reyes | | 561 | 552 | 9 |
| 2008-08-14 | vs BAL | 120 | L 6-11 | 54-66 | 4 | 22,140 | Zach Jackson | Daniel Cabrera | Fernando Cabrera | Rafael Perez | | 567 | 563 | 4 |
| 2008-08-15 | vs ANA | 121 | W 3-2 | 55-66 | 4 | 30,962 | Cliff Lee | Jered Weaver | Cliff Lee | Jose Arredondo | | 570 | 565 | 5 |
| 2008-08-16 | vs ANA | 122 | L 3-4 | 55-67 | 4 | 33,051 | Fausto Carmona | John Lackey | John Lackey | Fausto Carmona | Francisco Rodriguez | 573 | 569 | 4 |
| 2008-08-17 | vs ANA | 123 | W 4-3 | 56-67 | 4 | 28,356 | Jeremy Sowers | Joe Saunders | Jeremy Sowers | Justin Speier | Jensen Lewis | 577 | 572 | 5 |
| 2008-08-19 | vs KCA | 124 | W 9-4 | 57-67 | 4 | 18,946 | Anthony Reyes | Luke Hochevar | Anthony Reyes | Luke Hochevar | | 586 | 576 | 10 |
| 2008-08-20 | vs KCA | 125 | W 8-5 | 58-67 | 4 | 23,920 | Zach Jackson | Gil Meche | Juan Rincon | Joakim Soria | Jensen Lewis | 594 | 581 | 13 |
| 2008-08-21 | vs KCA | 126 | W 10-3 | 59-67 | 4 | 21,391 | Cliff Lee | Zack Greinke | Cliff Lee | Zack Greinke | | 604 | 584 | 20 |
| 2008-08-22 | @ TEX | 127 | W 7-5 | 60-67 | 4 | 20,535 | Fausto Carmona | Matt Harrison | Fausto Carmona | Matt Harrison | Jensen Lewis | 611 | 589 | 22 |
| 2008-08-23 | @ TEX | 128 | W 8-7 | 61-67 | 4 | 29,900 | Jeremy Sowers | Brandon McCarthy | Rafael Perez | Jamey Wright | Jensen Lewis | 619 | 596 | 23 |
| 2008-08-24 | @ TEX | 129 | W 4-3 | 62-67 | 4 | 14,956 | Anthony Reyes | Vicente Padilla | Rafael Betancourt | Eddie Guardado | | 623 | 599 | 24 |
| 2008-08-25 | @ DET | 130 | W 4-3 | 63-67 | 4 | 39,196 | Zach Jackson | Armando Galarraga | Brendan Donnelly | Gary Glover | Jensen Lewis | 627 | 602 | 25 |
| 2008-08-26 | @ DET | 131 | W 10-4 | 64-67 | 3 | 38,774 | Cliff Lee | Chris Lambert | Cliff Lee | Chris Lambert | | 637 | 606 | 31 |
| 2008-08-27 | @ DET | 132 | W 9-7 | 65-67 | 3 | 38,519 | Fausto Carmona | Justin Verlander | Fausto Carmona | Justin Verlander | | 646 | 613 | 33 |
| 2008-08-29 | vs SEA | 133 | L 2-3 | 65-68 | 3 | 26,047 | Jeremy Sowers | Felix Hernandez | Felix Hernandez | Jeremy Sowers | J.J. Putz | 648 | 616 | 32 |
| 2008-08-30 | vs SEA | 134 | L 3-4 | 65-69 | 3 | 33,387 | Anthony Reyes | Jarrod Washburn | J.J. Putz | Jensen Lewis | Randy Messenger | 651 | 620 | 31 |
| 2008-08-31 | vs SEA | 135 | L 4-6 | 65-70 | 4 | 35,376 | Zach Jackson | Ryan Rowland-Smith | Ryan Rowland-Smith | Zach Jackson | Roy Corcoran | 655 | 626 | 29 |
| 2008-09-01 | vs CHA | 136 | W 5-0 | 66-70 | 3 | 23,317 | Cliff Lee | Clayton Richard | Cliff Lee | Clayton Richard | | 660 | 626 | 34 |
| 2008-09-02 | vs CHA | 137 | W 9-3 | 67-70 | 3 | 20,980 | Fausto Carmona | John Danks | Fausto Carmona | John Danks | | 669 | 629 | 40 |
| 2008-09-03 | vs CHA | 138 | L 2-4 | 67-71 | 3 | 20,328 | Jeremy Sowers | Javier Vazquez | Javier Vazquez | Jeremy Sowers | Bobby Jenks | 671 | 633 | 38 |
| 2008-09-05 | @ KCA | 139 | W 9-3 | 68-71 | 3 | 21,107 | Anthony Reyes | Brandon Duckworth | Edward Mujica | Brandon Duckworth | | 680 | 636 | 44 |
| 2008-09-06 | @ KCA | 140 | L 1-3 | 68-72 | 3 | 18,795 | Zach Jackson | Gil Meche | Gil Meche | Zach Jackson | Joakim Soria | 681 | 639 | 42 |
| 2008-09-07 | @ KCA | 141 | W 3-1 | 69-72 | 3 | 15,023 | Cliff Lee | Zack Greinke | Cliff Lee | Zack Greinke | Jensen Lewis | 684 | 640 | 44 |
| 2008-09-08 | @ BAL | 142 | L 3-14 | 69-73 | 4 | 11,181 | Fausto Carmona | Garrett Olson | Garrett Olson | Fausto Carmona | | 687 | 654 | 33 |
| 2008-09-09 | @ BAL | 143 | W 6-1 | 70-73 | 3 | 14,900 | Jeremy Sowers | Radhames Liz | Jeremy Sowers | Radhames Liz | | 693 | 655 | 38 |
| 2008-09-10 | @ BAL | 144 | W 7-1 | 71-73 | 3 | 12,438 | Scott Lewis | Chris Waters | Scott Lewis | Chris Waters | | 700 | 656 | 44 |
| 2008-09-11 | @ BAL | 145 | L 3-6 | 71-74 | 3 | 12,526 | Zach Jackson | Brian Bass | Lance Cormier | Zach Jackson | Jim Miller | 703 | 662 | 41 |
| 2008-09-12 | vs KCA | 146 | W 12-5 | 72-74 | 3 | 32,843 | Cliff Lee | Gil Meche | Cliff Lee | Gil Meche | | 715 | 667 | 48 |
| 2008-09-13 | vs KCA | 147 | L 3-8 | 72-76 | 3 | 25,783 | Fausto Carmona | Zack Greinke | Zack Greinke | Fausto Carmona | | 718 | 675 | 43 |
| 2008-09-13 | vs KCA | 148 | L 4-8 | 72-76 | 3 | 25,485 | Bryan Bullington | Rob Tejeda | Rob Tejeda | Bryan Bullington | Joakim Soria | 722 | 683 | 39 |
| 2008-09-14 | vs KCA | 149 | L 3-13 | 72-77 | 3 | 29,530 | Jeremy Sowers | Brian Bannister | Brian Bannister | Edward Mujica | | 725 | 696 | 29 |
| 2008-09-15 | vs MIN | 150 | W 3-1 | 73-77 | 3 | 19,607 | Scott Lewis | Kevin Slowey | Scott Lewis | Kevin Slowey | Jensen Lewis | 728 | 697 | 31 |
| 2008-09-16 | vs MIN | 151 | W 12-9 | 74-77 | 3 | 21,295 | Zach Jackson | Francisco Liriano | Tom Mastny | Joe Nathan | | 740 | 706 | 34 |
| 2008-09-17 | vs MIN | 152 | W 6-4 | 75-77 | 3 | 22,904 | Cliff Lee | Scott Baker | Edward Mujica | Jose Mijares | Jensen Lewis | 746 | 710 | 36 |
| 2008-09-19 | vs DET | 153 | W 6-5 | 76-77 | 3 | 33,733 | Fausto Carmona | Armando Galarraga | Rafael Perez | Freddy Dolsi | | 752 | 715 | 37 |
| 2008-09-20 | vs DET | 154 | W 6-3 | 77-77 | 3 | 36,869 | Jeremy Sowers | Justin Verlander | Jeremy Sowers | Justin Verlander | Jensen Lewis | 758 | 718 | 40 |
| 2008-09-21 | vs DET | 155 | W 10-5 | 78-77 | 3 | 36,957 | Scott Lewis | Dontrelle Willis | Scott Lewis | Dontrelle Willis | | 768 | 723 | 45 |
| 2008-09-22 | @ BOS | 156 | W 4-3 | 79-77 | 3 | 37,828 | Zach Jackson | Josh Beckett | Zach Jackson | Josh Beckett | Jensen Lewis | 772 | 726 | 46 |
| 2008-09-23 | @ BOS | 157 | L 4-5 | 79-78 | 3 | 37,882 | Cliff Lee | Tim Wakefield | Tim Wakefield | Cliff Lee | Jonathan Papelbon | 776 | 731 | 45 |
| 2008-09-24 | @ BOS | 158 | L 4-5 | 79-79 | 3 | 37,719 | Fausto Carmona | Paul Byrd | David Aardsma | Rafael Perez | Manny Delcarmen | 780 | 736 | 44 |
| 2008-09-25 | @ BOS | 159 | L 1-6 | 79-80 | 3 | 37,726 | Jeremy Sowers | Jon Lester | Jon Lester | Jeremy Sowers | | 781 | 742 | 39 |
| 2008-09-26 | @ CHA | 160 | W 11-8 | 80-80 | 3 | 36,494 | Scott Lewis | John Danks | Scott Lewis | John Danks | Jensen Lewis | 792 | 750 | 42 |
| 2008-09-27 | @ CHA | 161 | W 12-6 | 81-80 | 3 | 36,031 | Zach Jackson | Javier Vazquez | Zach Jackson | Javier Vazquez | | 804 | 756 | 48 |
| 2008-09-28 | @ CHA | 162 | L 1-5 | 81-81 | 3 | 33,396 | Bryan Bullington | Mark Buehrle | Mark Buehrle | Bryan Bullington | | 805 | 761 | 44 |