| 2008-03-25 | vs BOS | 1 | L 5-6 | 0-1 | 2 | 44,628 | Joe Blanton | Daisuke Matsuzaka | Hideki Okajima | Huston Street | Jonathan Papelbon | 5 | 6 | -1 |
| 2008-03-26 | vs BOS | 2 | W 5-1 | 1-1 | 1 | 44,735 | Rich Harden | Jon Lester | Rich Harden | Jon Lester | | 10 | 7 | 3 |
| 2008-04-01 | vs BOS | 3 | L 1-2 | 1-2 | 4 | 36,067 | Joe Blanton | Daisuke Matsuzaka | Daisuke Matsuzaka | Joe Blanton | Jonathan Papelbon | 11 | 9 | 2 |
| 2008-04-02 | vs BOS | 4 | L 0-5 | 1-3 | 4 | 21,625 | Rich Harden | Jon Lester | Jon Lester | Alan Embree | | 11 | 14 | -3 |
| 2008-04-04 | vs CLE | 5 | W 6-3 | 2-3 | 4 | 13,916 | Justin Duchscherer | Paul Byrd | Justin Duchscherer | Paul Byrd | | 17 | 17 | 0 |
| 2008-04-05 | vs CLE | 6 | W 6-1 | 3-3 | 2 | 16,279 | Dana Eveland | CC Sabathia | Dana Eveland | CC Sabathia | | 23 | 18 | 5 |
| 2008-04-06 | vs CLE | 7 | L 1-2 | 3-4 | 3 | 16,384 | Joe Blanton | Cliff Lee | Cliff Lee | Joe Blanton | Joe Borowski | 24 | 20 | 4 |
| 2008-04-08 | @ TOR | 8 | W 9-8 | 4-4 | 2 | 31,336 | Chad Gaudin | A.J. Burnett | Alan Embree | Jeremy Accardo | Huston Street | 33 | 28 | 5 |
| 2008-04-09 | @ TOR | 9 | W 6-3 | 5-4 | 2 | 16,102 | Greg Smith | Dustin McGowan | Fernando Hernandez | Jeremy Accardo | Huston Street | 39 | 31 | 8 |
| 2008-04-10 | @ TOR | 10 | W 3-2 | 6-4 | 2 | 16,521 | Dana Eveland | Shaun Marcum | Joey Devine | Brandon League | Keith Foulke | 42 | 33 | 9 |
| 2008-04-11 | @ CLE | 11 | W 9-7 | 7-4 | 1 | 17,859 | Joe Blanton | CC Sabathia | Joe Blanton | CC Sabathia | Huston Street | 51 | 40 | 11 |
| 2008-04-12 | @ CLE | 12 | W 7-3 | 8-4 | 1 | 19,170 | Lenny DiNardo | Fausto Carmona | Lenny DiNardo | Fausto Carmona | | 58 | 43 | 15 |
| 2008-04-13 | @ CLE | 13 | L 1-7 | 8-5 | 1 | 17,228 | Chad Gaudin | Cliff Lee | Cliff Lee | Chad Gaudin | | 59 | 50 | 9 |
| 2008-04-14 | @ CHA | 14 | W 2-1 | 9-5 | 1 | 20,430 | Greg Smith | Mark Buehrle | Greg Smith | Mark Buehrle | Huston Street | 61 | 51 | 10 |
| 2008-04-15 | @ CHA | 15 | L 1-4 | 9-6 | 2 | 18,254 | Dana Eveland | John Danks | John Danks | Dana Eveland | Bobby Jenks | 62 | 55 | 7 |
| 2008-04-16 | vs SEA | 16 | L 2-4 | 9-7 | 2 | 21,126 | Joe Blanton | Felix Hernandez | Felix Hernandez | Joe Blanton | | 64 | 59 | 5 |
| 2008-04-17 | vs SEA | 17 | L 1-8 | 9-8 | 2 | 10,164 | Lenny DiNardo | Carlos Silva | Carlos Silva | Lenny DiNardo | | 65 | 67 | -2 |
| 2008-04-18 | vs KCA | 18 | W 13-2 | 10-8 | 2 | 12,528 | Chad Gaudin | Brian Bannister | Chad Gaudin | Brian Bannister | | 78 | 69 | 9 |
| 2008-04-19 | vs KCA | 19 | W 6-5 | 11-8 | 2 | 20,390 | Greg Smith | Zack Greinke | Joey Devine | Joel Peralta | Huston Street | 84 | 74 | 10 |
| 2008-04-20 | vs KCA | 20 | W 7-1 | 12-8 | 2 | 18,645 | Dana Eveland | Luke Hochevar | Dana Eveland | Luke Hochevar | | 91 | 75 | 16 |
| 2008-04-22 | vs MIN | 21 | L 4-5 | 12-9 | 2 | 10,267 | Joe Blanton | Livan Hernandez | Juan Rincon | Joe Blanton | Joe Nathan | 95 | 80 | 15 |
| 2008-04-23 | vs MIN | 22 | W 3-0 | 13-9 | 2 | 15,242 | Chad Gaudin | Boof Bonser | Chad Gaudin | Boof Bonser | Huston Street | 98 | 80 | 18 |
| 2008-04-24 | vs MIN | 23 | W 11-2 | 14-9 | 2 | 12,593 | Greg Smith | Francisco Liriano | Greg Smith | Francisco Liriano | | 109 | 82 | 27 |
| 2008-04-25 | @ SEA | 24 | W 4-3 | 15-9 | 2 | 40,845 | Dana Eveland | Miguel Batista | Dana Eveland | Miguel Batista | Huston Street | 113 | 85 | 28 |
| 2008-04-26 | @ SEA | 25 | L 3-5 | 15-10 | 2 | 37,563 | Justin Duchscherer | Erik Bedard | Erik Bedard | Justin Duchscherer | | 116 | 90 | 26 |
| 2008-04-27 | @ SEA | 26 | W 4-2 | 16-10 | 2 | 32,612 | Joe Blanton | Felix Hernandez | Joe Blanton | Felix Hernandez | Huston Street | 120 | 92 | 28 |
| 2008-04-28 | @ ANA | 27 | W 14-2 | 17-10 | 1 | 37,725 | Chad Gaudin | Jon Garland | Chad Gaudin | Jon Garland | | 134 | 94 | 40 |
| 2008-04-29 | @ ANA | 28 | L 0-2 | 17-11 | 2 | 35,764 | Greg Smith | Joe Saunders | Joe Saunders | Greg Smith | Francisco Rodriguez | 134 | 96 | 38 |
| 2008-04-30 | @ ANA | 29 | L 1-6 | 17-12 | 2 | 35,301 | Dana Eveland | Ervin Santana | Ervin Santana | Dana Eveland | | 135 | 102 | 33 |
| 2008-05-01 | @ ANA | 30 | W 15-8 | 18-12 | 2 | 37,396 | Justin Duchscherer | Nick Adenhart | Justin Duchscherer | Dustin Moseley | | 150 | 110 | 40 |
| 2008-05-02 | vs TEX | 31 | L 3-4 | 18-13 | 2 | 15,408 | Joe Blanton | Vicente Padilla | Vicente Padilla | Joe Blanton | C.J. Wilson | 153 | 114 | 39 |
| 2008-05-03 | vs TEX | 32 | L 3-6 | 18-14 | 2 | 20,524 | Chad Gaudin | A.J. Murray | A.J. Murray | Chad Gaudin | Joaquin Benoit | 156 | 120 | 36 |
| 2008-05-04 | vs TEX | 33 | W 3-1 | 19-14 | 2 | 31,673 | Greg Smith | Scott Feldman | Santiago Casilla | Scott Feldman | Huston Street | 159 | 121 | 38 |
| 2008-05-05 | vs BAL | 34 | W 2-1 | 20-14 | 2 | 10,128 | Dana Eveland | Garrett Olson | Joey Devine | Jim Johnson | | 161 | 122 | 39 |
| 2008-05-06 | vs BAL | 35 | W 4-2 | 21-14 | 2 | 11,492 | Justin Duchscherer | Brian Burres | Justin Duchscherer | Brian Burres | Santiago Casilla | 165 | 124 | 41 |
| 2008-05-07 | vs BAL | 36 | W 6-5 | 22-14 | 2 | 15,235 | Joe Blanton | Jeremy Guthrie | Dallas Braden | Lance Cormier | | 171 | 129 | 42 |
| 2008-05-09 | @ TEX | 37 | L 0-4 | 22-15 | 2 | 23,516 | Greg Smith | Scott Feldman | Scott Feldman | Greg Smith | | 171 | 133 | 38 |
| 2008-05-10 | @ TEX | 38 | L 4-6 | 22-16 | 2 | 22,899 | Dana Eveland | Kevin Millwood | Josh Rupe | Dana Eveland | | 175 | 139 | 36 |
| 2008-05-11 | @ TEX | 39 | W 12-6 | 23-16 | 1 | 23,959 | Rich Harden | Sidney Ponson | Santiago Casilla | Franklyn German | | 187 | 145 | 42 |
| 2008-05-13 | @ CLE | 40 | L 0-4 | 23-17 | 2 | 16,974 | Justin Duchscherer | Paul Byrd | Paul Byrd | Justin Duchscherer | Masahide Kobayashi | 187 | 149 | 38 |
| 2008-05-14 | @ CLE | 41 | L 0-2 | 23-18 | 2 | 18,188 | Joe Blanton | CC Sabathia | CC Sabathia | Joe Blanton | | 187 | 151 | 36 |
| 2008-05-15 | @ CLE | 42 | L 2-4 | 23-19 | 2 | 26,764 | Greg Smith | Aaron Laffey | Aaron Laffey | Greg Smith | Masahide Kobayashi | 189 | 155 | 34 |
| 2008-05-16 | @ ATL | 43 | L 2-3 | 23-20 | 2 | 31,004 | Dana Eveland | Jair Jurrjens | Manny Acosta | Alan Embree | | 191 | 158 | 33 |
| 2008-05-17 | @ ATL | 44 | W 5-4 | 24-20 | 2 | 38,324 | Rich Harden | Tim Hudson | Rich Harden | Tim Hudson | | 196 | 162 | 34 |
| 2008-05-18 | @ ATL | 45 | L 2-5 | 24-21 | 2 | 31,025 | Justin Duchscherer | Jo-Jo Reyes | Jo-Jo Reyes | Justin Duchscherer | | 198 | 167 | 31 |
| 2008-05-19 | vs TBA | 46 | L 6-7 | 24-22 | 2 | 11,077 | Joe Blanton | James Shields | Jason Hammel | Chad Gaudin | Troy Percival | 204 | 174 | 30 |
| 2008-05-20 | vs TBA | 47 | L 2-3 | 24-23 | 2 | 11,272 | Greg Smith | Scott Kazmir | Scott Kazmir | Greg Smith | Troy Percival | 206 | 177 | 29 |
| 2008-05-21 | vs TBA | 48 | W 9-1 | 25-23 | 2 | 22,712 | Dana Eveland | Andy Sonnanstine | Dana Eveland | Andy Sonnanstine | | 215 | 178 | 37 |
| 2008-05-23 | vs BOS | 49 | W 8-3 | 26-23 | 2 | 29,057 | Rich Harden | Tim Wakefield | Rich Harden | Tim Wakefield | | 223 | 181 | 42 |
| 2008-05-24 | vs BOS | 50 | W 3-0 | 27-23 | 2 | 33,468 | Justin Duchscherer | Josh Beckett | Justin Duchscherer | Josh Beckett | Huston Street | 226 | 181 | 45 |
| 2008-05-25 | vs BOS | 51 | W 6-3 | 28-23 | 2 | 35,067 | Joe Blanton | Jon Lester | Joe Blanton | Jon Lester | Huston Street | 232 | 184 | 48 |
| 2008-05-27 | vs TOR | 52 | W 3-1 | 29-23 | 2 | 10,635 | Greg Smith | A.J. Burnett | Greg Smith | A.J. Burnett | Huston Street | 235 | 185 | 50 |
| 2008-05-28 | vs TOR | 53 | L 1-2 | 29-24 | 2 | 17,460 | Rich Harden | Roy Halladay | Roy Halladay | Keith Foulke | B.J. Ryan | 236 | 187 | 49 |
| 2008-05-29 | vs TOR | 54 | L 0-12 | 29-25 | 2 | 21,862 | Dana Eveland | Jesse Litsch | Jesse Litsch | Dana Eveland | | 236 | 199 | 37 |
| 2008-05-30 | @ TEX | 55 | L 1-3 | 29-26 | 2 | 21,763 | Justin Duchscherer | Kevin Millwood | Kevin Millwood | Justin Duchscherer | C.J. Wilson | 237 | 202 | 35 |
| 2008-05-31 | @ TEX | 56 | L 4-8 | 29-27 | 2 | 36,798 | Joe Blanton | Sidney Ponson | Sidney Ponson | Joe Blanton | | 241 | 210 | 31 |
| 2008-06-01 | @ TEX | 57 | W 13-8 | 30-27 | 2 | 17,661 | Greg Smith | Scott Feldman | Chad Gaudin | Jamey Wright | | 254 | 218 | 36 |
| 2008-06-02 | vs DET | 58 | W 3-2 | 31-27 | 2 | 11,772 | Rich Harden | Kenny Rogers | Huston Street | Francisco Cruceta | | 257 | 220 | 37 |
| 2008-06-03 | vs DET | 59 | W 5-4 | 32-27 | 2 | 10,871 | Dana Eveland | Dontrelle Willis | Chad Gaudin | Bobby Seay | | 262 | 224 | 38 |
| 2008-06-04 | vs DET | 60 | W 10-2 | 33-27 | 2 | 19,258 | Justin Duchscherer | Nate Robertson | Justin Duchscherer | Nate Robertson | | 272 | 226 | 46 |
| 2008-06-06 | vs ANA | 61 | L 1-3 | 33-28 | 2 | 25,120 | Joe Blanton | John Lackey | John Lackey | Joe Blanton | Francisco Rodriguez | 273 | 229 | 44 |
| 2008-06-07 | vs ANA | 62 | L 3-5 | 33-29 | 2 | 29,294 | Greg Smith | Jon Garland | Jon Garland | Greg Smith | Francisco Rodriguez | 276 | 234 | 42 |
| 2008-06-08 | vs ANA | 63 | W 7-3 | 34-29 | 2 | 26,332 | Rich Harden | Ervin Santana | Brad Ziegler | Chris Bootcheck | | 283 | 237 | 46 |
| 2008-06-10 | vs NYA | 64 | L 1-3 | 34-30 | 2 | 26,402 | Dana Eveland | Chien-Ming Wang | Chien-Ming Wang | Dana Eveland | Mariano Rivera | 284 | 240 | 44 |
| 2008-06-11 | vs NYA | 65 | W 8-4 | 35-30 | 2 | 27,292 | Justin Duchscherer | Darrell Rasner | Justin Duchscherer | Darrell Rasner | | 292 | 244 | 48 |
| 2008-06-12 | vs NYA | 66 | L 1-4 | 35-31 | 2 | 28,658 | Joe Blanton | Andy Pettitte | Andy Pettitte | Joe Blanton | Mariano Rivera | 293 | 248 | 45 |
| 2008-06-13 | @ SFN | 67 | W 5-1 | 36-31 | 2 | 42,445 | Greg Smith | Barry Zito | Greg Smith | Barry Zito | | 298 | 249 | 49 |
| 2008-06-14 | @ SFN | 68 | W 4-0 | 37-31 | 2 | 40,873 | Rich Harden | Matt Cain | Rich Harden | Matt Cain | | 302 | 249 | 53 |
| 2008-06-15 | @ SFN | 69 | W 5-3 | 38-31 | 2 | 41,547 | Dana Eveland | Kevin Correia | Dana Eveland | Kevin Correia | Huston Street | 307 | 252 | 55 |
| 2008-06-17 | @ ARI | 70 | W 15-1 | 39-31 | 2 | 28,710 | Justin Duchscherer | Brandon Webb | Justin Duchscherer | Brandon Webb | | 322 | 253 | 69 |
| 2008-06-18 | @ ARI | 71 | L 1-11 | 39-32 | 2 | 28,507 | Joe Blanton | Dan Haren | Dan Haren | Joe Blanton | | 323 | 264 | 59 |
| 2008-06-19 | @ ARI | 72 | L 1-2 | 39-33 | 2 | 31,997 | Greg Smith | Doug Davis | Tony Pena | Keith Foulke | Brandon Lyon | 324 | 266 | 58 |
| 2008-06-20 | vs FLO | 73 | W 7-6 | 40-33 | 2 | 15,035 | Rich Harden | Mark Hendrickson | Andrew Brown | Doug Waechter | | 331 | 272 | 59 |
| 2008-06-21 | vs FLO | 74 | L 4-6 | 40-34 | 2 | 19,287 | Dana Eveland | Ricky Nolasco | Renyel Pinto | Huston Street | Kevin Gregg | 335 | 278 | 57 |
| 2008-06-22 | vs FLO | 75 | W 7-1 | 41-34 | 2 | 22,461 | Justin Duchscherer | Andrew Miller | Justin Duchscherer | Andrew Miller | | 342 | 279 | 63 |
| 2008-06-24 | vs PHI | 76 | W 5-2 | 42-34 | 2 | 13,348 | Joe Blanton | Jamie Moyer | Joe Blanton | Jamie Moyer | Huston Street | 347 | 281 | 66 |
| 2008-06-25 | vs PHI | 77 | L 0-4 | 42-35 | 2 | 22,231 | Greg Smith | Kyle Kendrick | Kyle Kendrick | Greg Smith | | 347 | 285 | 62 |
| 2008-06-26 | vs PHI | 78 | W 5-0 | 43-35 | 2 | 17,228 | Rich Harden | Adam Eaton | Rich Harden | Adam Eaton | | 352 | 285 | 67 |
| 2008-06-27 | vs SFN | 79 | W 4-1 | 44-35 | 2 | 27,125 | Dana Eveland | Kevin Correia | Dana Eveland | Keiichi Yabu | Huston Street | 356 | 286 | 70 |
| 2008-06-28 | vs SFN | 80 | L 0-1 | 44-36 | 2 | 36,067 | Justin Duchscherer | Tim Lincecum | Tim Lincecum | Justin Duchscherer | Brian Wilson | 356 | 287 | 69 |
| 2008-06-29 | vs SFN | 81 | L 1-11 | 44-37 | 2 | 33,841 | Joe Blanton | Jonathan Sanchez | Jonathan Sanchez | Joe Blanton | | 357 | 298 | 59 |
| 2008-06-30 | @ ANA | 82 | W 6-1 | 45-37 | 2 | 42,046 | Greg Smith | Jon Garland | Greg Smith | Jon Garland | | 363 | 299 | 64 |
| 2008-07-01 | @ ANA | 83 | L 3-5 | 45-38 | 2 | 42,047 | Rich Harden | Ervin Santana | Scot Shields | Alan Embree | Francisco Rodriguez | 366 | 304 | 62 |
| 2008-07-02 | @ ANA | 84 | L 4-7 | 45-39 | 2 | 41,091 | Dana Eveland | Joe Saunders | Joe Saunders | Keith Foulke | Francisco Rodriguez | 370 | 311 | 59 |
| 2008-07-03 | @ CHA | 85 | W 3-2 | 46-39 | 2 | 26,730 | Justin Duchscherer | Javier Vazquez | Justin Duchscherer | Javier Vazquez | Huston Street | 373 | 313 | 60 |
| 2008-07-04 | @ CHA | 86 | W 7-1 | 47-39 | 2 | 29,600 | Joe Blanton | Mark Buehrle | Joe Blanton | Mark Buehrle | | 380 | 314 | 66 |
| 2008-07-05 | @ CHA | 87 | L 1-6 | 47-40 | 2 | 35,586 | Greg Smith | Gavin Floyd | Gavin Floyd | Greg Smith | | 381 | 320 | 61 |
| 2008-07-06 | @ CHA | 88 | L 3-4 | 47-41 | 2 | 31,955 | Rich Harden | John Danks | John Danks | Rich Harden | Scott Linebrink | 384 | 324 | 60 |
| 2008-07-07 | vs SEA | 89 | W 4-3 | 48-41 | 2 | 11,129 | Dana Eveland | Jarrod Washburn | Dana Eveland | Jarrod Washburn | Huston Street | 388 | 327 | 61 |
| 2008-07-08 | vs SEA | 90 | W 2-0 | 49-41 | 2 | 12,543 | Justin Duchscherer | Carlos Silva | Justin Duchscherer | Carlos Silva | | 390 | 327 | 63 |
| 2008-07-09 | vs SEA | 91 | L 4-6 | 49-42 | 2 | 21,128 | Joe Blanton | Miguel Batista | Roy Corcoran | Joe Blanton | Brandon Morrow | 394 | 333 | 61 |
| 2008-07-10 | vs SEA | 92 | W 3-2 | 50-42 | 2 | 15,187 | Greg Smith | R.A. Dickey | Huston Street | Cesar Jimenez | | 397 | 335 | 62 |
| 2008-07-11 | vs ANA | 93 | W 9-2 | 51-42 | 2 | 31,372 | Sean Gallagher | Jon Garland | Sean Gallagher | Jon Garland | | 406 | 337 | 69 |
| 2008-07-12 | vs ANA | 94 | L 1-4 | 51-43 | 2 | 27,161 | Dana Eveland | Ervin Santana | Ervin Santana | Dana Eveland | Francisco Rodriguez | 407 | 341 | 66 |
| 2008-07-13 | vs ANA | 95 | L 3-4 | 51-44 | 2 | 29,352 | Justin Duchscherer | Dustin Moseley | Jose Arredondo | Huston Street | Francisco Rodriguez | 410 | 345 | 65 |
| 2008-07-18 | @ NYA | 96 | L 1-7 | 51-45 | 2 | 54,145 | Greg Smith | Mike Mussina | Mike Mussina | Greg Smith | | 411 | 352 | 59 |
| 2008-07-19 | @ NYA | 97 | L 3-4 | 51-46 | 2 | 54,183 | Sean Gallagher | Joba Chamberlain | David Robertson | Lenny DiNardo | | 414 | 356 | 58 |
| 2008-07-20 | @ NYA | 98 | L 1-2 | 51-47 | 2 | 54,366 | Justin Duchscherer | Andy Pettitte | Andy Pettitte | Justin Duchscherer | Mariano Rivera | 415 | 358 | 57 |
| 2008-07-21 | @ TBA | 99 | L 0-4 | 51-48 | 3 | 12,428 | Dana Eveland | Scott Kazmir | Scott Kazmir | Dana Eveland | | 415 | 362 | 53 |
| 2008-07-22 | @ TBA | 100 | W 8-1 | 52-48 | 2 | 16,800 | Dallas Braden | Andy Sonnanstine | Dallas Braden | Andy Sonnanstine | | 423 | 363 | 60 |
| 2008-07-23 | @ TBA | 101 | L 3-4 | 52-49 | 2 | 23,437 | Greg Smith | James Shields | James Shields | Greg Smith | Troy Percival | 426 | 367 | 59 |
| 2008-07-25 | vs TEX | 102 | L 6-14 | 52-50 | 3 | 20,141 | Sean Gallagher | Vicente Padilla | Vicente Padilla | Jerry Blevins | | 432 | 381 | 51 |
| 2008-07-26 | vs TEX | 103 | L 4-9 | 52-51 | 3 | 20,653 | Justin Duchscherer | Matt Harrison | Matt Harrison | Justin Duchscherer | | 436 | 390 | 46 |
| 2008-07-27 | vs TEX | 104 | W 6-5 | 53-51 | 3 | 21,135 | Dana Eveland | Eric Hurley | Jerry Blevins | Eric Hurley | Huston Street | 442 | 395 | 47 |
| 2008-07-28 | vs KCA | 105 | L 2-4 | 53-52 | 3 | 12,464 | Dallas Braden | Zack Greinke | Zack Greinke | Dallas Braden | Joakim Soria | 444 | 399 | 45 |
| 2008-07-29 | vs KCA | 106 | L 2-5 | 53-53 | 3 | 12,182 | Greg Smith | Gil Meche | Gil Meche | Greg Smith | Joakim Soria | 446 | 404 | 42 |
| 2008-07-30 | vs KCA | 107 | L 3-4 | 53-54 | 3 | 26,272 | Sean Gallagher | Brian Bannister | Ramon Ramirez | Huston Street | Joakim Soria | 449 | 408 | 41 |
| 2008-08-01 | @ BOS | 108 | L 1-2 | 53-55 | 3 | 37,832 | Justin Duchscherer | Tim Wakefield | Mike Timlin | Alan Embree | | 450 | 410 | 40 |
| 2008-08-02 | @ BOS | 109 | L 2-12 | 53-56 | 3 | 37,838 | Dana Eveland | Jon Lester | Jon Lester | Dana Eveland | | 452 | 422 | 30 |
| 2008-08-03 | @ BOS | 110 | L 2-5 | 53-57 | 3 | 37,317 | Dallas Braden | Daisuke Matsuzaka | Daisuke Matsuzaka | Dallas Braden | Jonathan Papelbon | 454 | 427 | 27 |
| 2008-08-04 | @ TOR | 111 | L 1-6 | 53-58 | 3 | 24,761 | Sean Gallagher | Roy Halladay | Roy Halladay | Sean Gallagher | | 455 | 433 | 22 |
| 2008-08-05 | @ TOR | 112 | L 3-4 | 53-59 | 3 | 23,580 | Greg Smith | Scott Richmond | Jesse Carlson | Huston Street | | 458 | 437 | 21 |
| 2008-08-06 | @ TOR | 113 | L 1-5 | 53-60 | 3 | 29,256 | Gio Gonzalez | Shaun Marcum | Shaun Marcum | Gio Gonzalez | | 459 | 442 | 17 |
| 2008-08-07 | @ TOR | 114 | L 4-6 | 53-61 | 3 | 28,821 | Justin Duchscherer | A.J. Burnett | A.J. Burnett | Jerry Blevins | B.J. Ryan | 463 | 448 | 15 |
| 2008-08-08 | @ DET | 115 | W 4-2 | 54-61 | 3 | 41,457 | Dallas Braden | Kenny Rogers | Dallas Braden | Kenny Rogers | Brad Ziegler | 467 | 450 | 17 |
| 2008-08-09 | @ DET | 116 | L 2-10 | 54-62 | 3 | 41,308 | Dan Meyer | Armando Galarraga | Armando Galarraga | Dan Meyer | | 469 | 460 | 9 |
| 2008-08-10 | @ DET | 117 | L 1-6 | 54-63 | 3 | 40,743 | Greg Smith | Nate Robertson | Nate Robertson | Greg Smith | Fernando Rodney | 470 | 466 | 4 |
| 2008-08-12 | vs TBA | 118 | W 2-1 | 55-63 | 3 | 14,284 | Gio Gonzalez | Scott Kazmir | Gio Gonzalez | Scott Kazmir | Brad Ziegler | 472 | 467 | 5 |
| 2008-08-13 | vs TBA | 119 | L 2-3 | 55-64 | 3 | 21,438 | Justin Duchscherer | Andy Sonnanstine | Andy Sonnanstine | Justin Duchscherer | Troy Percival | 474 | 470 | 4 |
| 2008-08-14 | vs TBA | 120 | L 6-7 | 55-65 | 3 | 16,689 | Sean Gallagher | James Shields | Jason Hammel | Santiago Casilla | Trever Miller | 480 | 477 | 3 |
| 2008-08-15 | vs CHA | 121 | W 6-4 | 56-65 | 3 | 19,405 | Dallas Braden | Gavin Floyd | Huston Street | Horacio Ramirez | | 486 | 481 | 5 |
| 2008-08-16 | vs CHA | 122 | L 1-2 | 56-66 | 3 | 22,206 | Greg Smith | John Danks | John Danks | Greg Smith | Bobby Jenks | 487 | 483 | 4 |
| 2008-08-17 | vs CHA | 123 | L 1-13 | 56-67 | 3 | 28,843 | Gio Gonzalez | Javier Vazquez | Javier Vazquez | Gio Gonzalez | | 488 | 496 | -8 |
| 2008-08-18 | @ MIN | 124 | W 3-2 | 57-67 | 3 | 25,024 | Justin Duchscherer | Nick Blackburn | Kirk Saarloos | Nick Blackburn | Brad Ziegler | 491 | 498 | -7 |
| 2008-08-19 | @ MIN | 125 | L 2-13 | 57-68 | 3 | 35,256 | Sean Gallagher | Kevin Slowey | Kevin Slowey | Sean Gallagher | | 493 | 511 | -18 |
| 2008-08-20 | @ MIN | 126 | L 1-3 | 57-69 | 3 | 30,888 | Dallas Braden | Francisco Liriano | Francisco Liriano | Dallas Braden | Joe Nathan | 494 | 514 | -20 |
| 2008-08-21 | @ SEA | 127 | W 2-0 | 58-69 | 3 | 25,611 | Greg Smith | Ryan Rowland-Smith | Greg Smith | Ryan Rowland-Smith | Brad Ziegler | 496 | 514 | -18 |
| 2008-08-22 | @ SEA | 128 | L 5-7 | 58-70 | 3 | 26,603 | Gio Gonzalez | Ryan Feierabend | Roy Corcoran | Jerry Blevins | J.J. Putz | 501 | 521 | -20 |
| 2008-08-23 | @ SEA | 129 | W 5-1 | 59-70 | 3 | 34,145 | Dana Eveland | Jarrod Washburn | Dana Eveland | Jarrod Washburn | | 506 | 522 | -16 |
| 2008-08-24 | @ SEA | 130 | L 4-8 | 59-71 | 3 | 28,731 | Dan Meyer | Felix Hernandez | Felix Hernandez | Dan Meyer | J.J. Putz | 510 | 530 | -20 |
| 2008-08-25 | @ ANA | 131 | W 2-1 | 60-71 | 3 | 39,584 | Dallas Braden | Jered Weaver | Dallas Braden | Jered Weaver | Brad Ziegler | 512 | 531 | -19 |
| 2008-08-26 | @ ANA | 132 | L 1-5 | 60-72 | 3 | 37,431 | Greg Smith | John Lackey | John Lackey | Greg Smith | | 513 | 536 | -23 |
| 2008-08-27 | @ ANA | 133 | W 6-5 | 61-72 | 3 | 38,587 | Gio Gonzalez | Joe Saunders | Huston Street | Joe Saunders | Brad Ziegler | 519 | 541 | -22 |
| 2008-08-28 | vs MIN | 134 | W 3-2 | 62-72 | 3 | 12,357 | Dana Eveland | Nick Blackburn | Joey Devine | Craig Breslow | | 522 | 543 | -21 |
| 2008-08-29 | vs MIN | 135 | L 2-12 | 62-73 | 3 | 22,355 | Dan Meyer | Kevin Slowey | Kevin Slowey | Dan Meyer | Craig Breslow | 524 | 555 | -31 |
| 2008-08-30 | vs MIN | 136 | W 3-2 | 63-73 | 3 | 25,238 | Dallas Braden | Francisco Liriano | Huston Street | Joe Nathan | | 527 | 557 | -30 |
| 2008-08-31 | vs MIN | 137 | L 4-12 | 63-74 | 3 | 18,427 | Greg Smith | Scott Baker | Scott Baker | Greg Smith | | 531 | 569 | -38 |
| 2008-09-02 | @ KCA | 138 | L 2-5 | 63-75 | 3 | 11,143 | Gio Gonzalez | Zack Greinke | Zack Greinke | Gio Gonzalez | Joakim Soria | 533 | 574 | -41 |
| 2008-09-04 | @ KCA | 139 | L 4-5 | 63-77 | 3 | 0 | Dana Eveland | Brian Bannister | Joakim Soria | Joey Devine | | 537 | 579 | -42 |
| 2008-09-04 | @ KCA | 140 | L 6-9 | 63-77 | 3 | 12,791 | Dan Meyer | Kyle Davies | Kyle Davies | Dan Meyer | Ramon Ramirez | 543 | 588 | -45 |
| 2008-09-05 | @ BAL | 141 | W 11-2 | 64-77 | 3 | 14,984 | Dallas Braden | Chris Waters | Dallas Braden | Chris Waters | | 554 | 590 | -36 |
| 2008-09-06 | @ BAL | 142 | W 5-1 | 65-77 | 3 | 21,553 | Greg Smith | Daniel Cabrera | Greg Smith | Daniel Cabrera | | 559 | 591 | -32 |
| 2008-09-08 | @ DET | 143 | L 8-14 | 65-78 | 3 | 37,981 | Gio Gonzalez | Zach Miner | Casey Fossum | Gio Gonzalez | | 567 | 605 | -38 |
| 2008-09-09 | @ DET | 144 | W 3-2 | 66-78 | 3 | 37,240 | Dana Eveland | Nate Robertson | Joey Devine | Fernando Rodney | Brad Ziegler | 570 | 607 | -37 |
| 2008-09-10 | @ DET | 145 | W 5-2 | 67-78 | 3 | 37,194 | Sean Gallagher | Armando Galarraga | Huston Street | Armando Galarraga | Brad Ziegler | 575 | 609 | -34 |
| 2008-09-11 | vs TEX | 146 | L 1-6 | 67-79 | 3 | 10,566 | Dallas Braden | Dustin Nippert | Dustin Nippert | Dallas Braden | | 576 | 615 | -39 |
| 2008-09-12 | vs TEX | 147 | L 0-7 | 67-80 | 3 | 15,117 | Greg Smith | Matt Harrison | Matt Harrison | Greg Smith | | 576 | 622 | -46 |
| 2008-09-13 | vs TEX | 148 | W 7-1 | 68-80 | 3 | 21,102 | Josh Outman | Scott Feldman | Josh Outman | Scott Feldman | | 583 | 623 | -40 |
| 2008-09-14 | vs TEX | 149 | W 7-4 | 69-80 | 3 | 18,551 | Dana Eveland | Vicente Padilla | Joey Devine | Warner Madrigal | Brad Ziegler | 590 | 627 | -37 |
| 2008-09-16 | vs ANA | 150 | W 8-1 | 70-80 | 3 | 14,325 | Sean Gallagher | John Lackey | Sean Gallagher | John Lackey | | 598 | 628 | -30 |
| 2008-09-17 | vs ANA | 151 | W 3-2 | 71-80 | 3 | 20,102 | Greg Smith | Jered Weaver | Brad Ziegler | Francisco Rodriguez | | 601 | 630 | -29 |
| 2008-09-18 | vs ANA | 152 | L 4-6 | 71-81 | 3 | 12,645 | Josh Outman | Joe Saunders | Joe Saunders | Josh Outman | Francisco Rodriguez | 605 | 636 | -31 |
| 2008-09-19 | vs SEA | 153 | W 2-0 | 72-81 | 3 | 30,149 | Dana Eveland | Felix Hernandez | Dana Eveland | Felix Hernandez | Brad Ziegler | 607 | 636 | -29 |
| 2008-09-20 | vs SEA | 154 | W 8-7 | 73-81 | 3 | 18,756 | Kirk Saarloos | Carlos Silva | Huston Street | Justin Thomas | Brad Ziegler | 615 | 643 | -28 |
| 2008-09-21 | vs SEA | 155 | W 5-3 | 74-81 | 3 | 18,707 | Sean Gallagher | Brandon Morrow | Brad Ziegler | Miguel Batista | Joey Devine | 620 | 646 | -26 |
| 2008-09-22 | @ TEX | 156 | W 4-3 | 75-81 | 2 | 14,925 | Greg Smith | Kevin Millwood | Alan Embree | Luis Mendoza | Santiago Casilla | 624 | 649 | -25 |
| 2008-09-23 | @ TEX | 157 | L 4-6 | 75-82 | 3 | 18,408 | Josh Outman | Dustin Nippert | Jamey Wright | Alan Embree | Frank Francisco | 628 | 655 | -27 |
| 2008-09-24 | @ TEX | 158 | L 4-14 | 75-83 | 3 | 16,832 | Dana Eveland | Matt Harrison | Matt Harrison | Dana Eveland | | 632 | 669 | -37 |
| 2008-09-26 | @ SEA | 159 | L 8-10 | 75-84 | 3 | 24,662 | Sean Gallagher | Brandon Morrow | Brandon Morrow | Sean Gallagher | Roy Corcoran | 640 | 679 | -39 |
| 2008-09-27 | @ SEA | 160 | L 3-7 | 75-85 | 3 | 24,440 | Greg Smith | Ryan Rowland-Smith | Ryan Rowland-Smith | Greg Smith | Sean Green | 643 | 686 | -43 |
| 2008-09-28 | @ SEA | 161 | L 3-4 | 75-86 | 3 | 27,110 | Josh Outman | R.A. Dickey | R.A. Dickey | Josh Outman | J.J. Putz | 646 | 690 | -44 |