| 2000-04-03 | vs TBA | 1 | L 0-7 | 0-1 | 5 | 43,830 | Brad Radke | Steve Trachsel | Steve Trachsel | Brad Radke | | 0 | 7 | -7 |
| 2000-04-04 | vs TBA | 2 | W 6-5 | 1-1 | 3 | 7,020 | Eric Milton | Ryan Rupe | Hector Carrasco | Roberto Hernandez | | 6 | 12 | -6 |
| 2000-04-05 | vs TBA | 3 | W 10-7 | 2-1 | 1 | 7,089 | Sean Bergman | Esteban Yan | Eddie Guardado | Rick White | | 16 | 19 | -3 |
| 2000-04-06 | vs TBA | 4 | L 6-7 | 2-2 | 3 | 8,763 | Joe Mays | Dan Wheeler | Jim Mecir | Hector Carrasco | Roberto Hernandez | 22 | 26 | -4 |
| 2000-04-07 | @ KCA | 5 | L 6-10 | 2-3 | 4 | 40,474 | Johan Santana | Mac Suzuki | Chris Fussell | Travis Miller | | 28 | 36 | -8 |
| 2000-04-08 | @ KCA | 6 | L 2-5 | 2-4 | 4 | 17,133 | Brad Radke | Jeff Suppan | Jeff Suppan | Brad Radke | Jose Santiago | 30 | 41 | -11 |
| 2000-04-09 | @ KCA | 7 | W 13-7 | 3-4 | 4 | 20,480 | Eric Milton | Jay Witasick | Eric Milton | Jay Witasick | | 43 | 48 | -5 |
| 2000-04-10 | @ KCA | 8 | L 5-6 | 3-5 | 4 | 13,252 | Sean Bergman | Jose Rosado | Ricky Bottalico | LaTroy Hawkins | | 48 | 54 | -6 |
| 2000-04-11 | @ BOS | 9 | L 4-13 | 3-6 | 4 | 33,114 | Joe Mays | Ramon Martinez | Ramon Martinez | Joe Mays | | 52 | 67 | -15 |
| 2000-04-12 | @ BOS | 10 | L 3-7 | 3-7 | 4 | 20,313 | Johan Santana | Jeff Fassero | Jeff Fassero | Johan Santana | | 55 | 74 | -19 |
| 2000-04-13 | @ BOS | 11 | L 3-4 | 3-8 | 5 | 22,194 | Brad Radke | Pete Schourek | Tim Wakefield | Bob Wells | Derek Lowe | 58 | 78 | -20 |
| 2000-04-14 | vs BAL | 12 | W 10-9 | 4-8 | 5 | 15,249 | Eric Milton | Jose Mercedes | Mark Redman | Buddy Groom | Eddie Guardado | 68 | 87 | -19 |
| 2000-04-15 | vs BAL | 13 | L 4-6 | 4-9 | 5 | 18,745 | Sean Bergman | Calvin Maduro | Tim Worrell | Travis Miller | Mike Trombley | 72 | 93 | -21 |
| 2000-04-16 | vs BAL | 14 | L 0-5 | 4-10 | 5 | 14,066 | Joe Mays | Sidney Ponson | Sidney Ponson | Joe Mays | | 72 | 98 | -26 |
| 2000-04-18 | vs KCA | 15 | W 3-1 | 5-10 | 4 | 6,630 | Brad Radke | Jeff Suppan | Brad Radke | Jeff Suppan | Bob Wells | 75 | 99 | -24 |
| 2000-04-19 | vs KCA | 16 | W 7-6 | 6-10 | 4 | 7,606 | Eric Milton | Mac Suzuki | Hector Carrasco | Jose Santiago | | 82 | 105 | -23 |
| 2000-04-20 | vs KCA | 17 | W 9-7 | 7-10 | 4 | 9,213 | Sean Bergman | Jose Rosado | Sean Bergman | Jose Rosado | Bob Wells | 91 | 112 | -21 |
| 2000-04-21 | @ TEX | 18 | W 10-5 | 8-10 | 4 | 35,155 | Joe Mays | Mark Clark | Hector Carrasco | Mark Clark | | 101 | 117 | -16 |
| 2000-04-22 | @ TEX | 19 | L 3-8 | 8-11 | 4 | 42,659 | Johan Santana | Esteban Loaiza | Esteban Loaiza | Johan Santana | | 104 | 125 | -21 |
| 2000-04-23 | @ TEX | 20 | W 5-4 | 9-11 | 3 | 30,081 | Brad Radke | Darren Oliver | Brad Radke | Darren Oliver | Bob Wells | 109 | 129 | -20 |
| 2000-04-24 | @ NYA | 21 | W 7-3 | 10-11 | 3 | 35,693 | Eric Milton | Roger Clemens | Eric Milton | Roger Clemens | | 116 | 132 | -16 |
| 2000-04-25 | @ NYA | 22 | W 6-1 | 11-11 | 3 | 27,372 | Sean Bergman | Ramiro Mendoza | Sean Bergman | Ramiro Mendoza | | 122 | 133 | -11 |
| 2000-04-26 | @ NYA | 23 | L 0-2 | 11-12 | 3 | 27,919 | Joe Mays | Andy Pettitte | Jeff Nelson | Joe Mays | Mariano Rivera | 122 | 135 | -13 |
| 2000-04-28 | vs OAK | 24 | L 2-5 | 11-13 | 4 | 10,611 | Brad Radke | Gil Heredia | Gil Heredia | Brad Radke | Jason Isringhausen | 124 | 140 | -16 |
| 2000-04-29 | vs OAK | 25 | L 2-6 | 11-14 | 4 | 15,803 | Eric Milton | Mark Mulder | T.J. Mathews | Eddie Guardado | | 126 | 146 | -20 |
| 2000-04-30 | vs OAK | 26 | L 2-8 | 11-15 | 4 | 10,682 | Sean Bergman | Tim Hudson | Tim Hudson | Sean Bergman | | 128 | 154 | -26 |
| 2000-05-02 | vs SEA | 27 | L 4-5 | 11-16 | 4 | 6,780 | Joe Mays | John Halama | John Halama | Joe Mays | Kazuhiro Sasaki | 132 | 159 | -27 |
| 2000-05-03 | vs SEA | 28 | W 5-4 | 12-16 | 4 | 6,596 | Brad Radke | Brett Tomko | Eddie Guardado | Jose Mesa | | 137 | 163 | -26 |
| 2000-05-04 | vs DET | 29 | L 6-8 | 12-17 | 4 | 6,675 | Eric Milton | Dave Mlicki | Matt Anderson | Bob Wells | Todd Jones | 143 | 171 | -28 |
| 2000-05-05 | vs DET | 30 | L 8-10 | 12-18 | 4 | 11,500 | Sean Bergman | Hideo Nomo | Danny Patterson | Hector Carrasco | Todd Jones | 151 | 181 | -30 |
| 2000-05-06 | vs DET | 31 | W 6-1 | 13-18 | 4 | 14,013 | Mark Redman | C.J. Nitkowski | Mark Redman | C.J. Nitkowski | | 157 | 182 | -25 |
| 2000-05-07 | vs DET | 32 | W 4-0 | 14-18 | 4 | 8,333 | Joe Mays | Mark Johnson | Joe Mays | Mark Johnson | | 161 | 182 | -21 |
| 2000-05-08 | vs CLE | 33 | L 2-3 | 14-19 | 4 | 7,309 | Brad Radke | Dave Burba | Ricardo Rincon | Bob Wells | Steve Karsay | 163 | 185 | -22 |
| 2000-05-09 | vs CLE | 34 | W 6-5 | 15-19 | 4 | 7,777 | Eric Milton | Chuck Finley | LaTroy Hawkins | Chuck Finley | Travis Miller | 169 | 190 | -21 |
| 2000-05-10 | vs CLE | 35 | W 10-9 | 16-19 | 4 | 9,505 | Sean Bergman | Charles Nagy | Eddie Guardado | Steve Karsay | | 179 | 199 | -20 |
| 2000-05-12 | @ CHA | 36 | W 4-3 | 17-19 | 4 | 12,526 | Joe Mays | Jim Parque | Travis Miller | Sean Lowe | Hector Carrasco | 183 | 202 | -19 |
| 2000-05-13 | @ CHA | 37 | L 3-4 | 17-20 | 4 | 22,545 | Mark Redman | Mike Sirotka | Kelly Wunsch | Bob Wells | | 186 | 206 | -20 |
| 2000-05-14 | @ CHA | 38 | L 3-5 | 17-21 | 4 | 29,177 | Brad Radke | James Baldwin | Kelly Wunsch | Brad Radke | Keith Foulke | 189 | 211 | -22 |
| 2000-05-15 | @ SEA | 39 | L 0-14 | 17-22 | 4 | 30,289 | Eric Milton | Aaron Sele | Aaron Sele | Eric Milton | | 189 | 225 | -36 |
| 2000-05-16 | @ SEA | 40 | L 5-9 | 17-23 | 4 | 25,672 | Sean Bergman | Gil Meche | Gil Meche | Sean Bergman | | 194 | 234 | -40 |
| 2000-05-17 | @ SEA | 41 | L 0-4 | 17-24 | 4 | 25,583 | Joe Mays | John Halama | John Halama | Joe Mays | | 194 | 238 | -44 |
| 2000-05-18 | @ OAK | 42 | W 10-5 | 18-24 | 4 | 8,746 | Mark Redman | Kevin Appier | Mark Redman | Luis Vizcaino | | 204 | 243 | -39 |
| 2000-05-19 | @ OAK | 43 | W 3-2 | 19-24 | 4 | 11,422 | Brad Radke | Gil Heredia | Brad Radke | Gil Heredia | | 207 | 245 | -38 |
| 2000-05-20 | @ OAK | 44 | W 3-0 | 20-24 | 4 | 17,546 | Eric Milton | Mark Mulder | Eric Milton | Mark Mulder | Eddie Guardado | 210 | 245 | -35 |
| 2000-05-21 | @ OAK | 45 | L 4-13 | 20-25 | 4 | 34,065 | Sean Bergman | Tim Hudson | Tim Hudson | Sean Bergman | | 214 | 258 | -44 |
| 2000-05-23 | vs ANA | 46 | L 4-7 | 20-26 | 4 | 9,032 | Joe Mays | Brian Cooper | Brian Cooper | Joe Mays | Troy Percival | 218 | 265 | -47 |
| 2000-05-24 | vs ANA | 47 | L 5-6 | 20-27 | 4 | 8,633 | Mark Redman | Jarrod Washburn | Troy Percival | Bob Wells | Al Levine | 223 | 271 | -48 |
| 2000-05-25 | vs ANA | 48 | L 1-3 | 20-28 | 4 | 13,552 | Brad Radke | Scott Schoeneweis | Scott Schoeneweis | Brad Radke | Troy Percival | 224 | 274 | -50 |
| 2000-05-26 | vs TEX | 49 | W 10-2 | 21-28 | 4 | 10,069 | Eric Milton | Darren Oliver | Eric Milton | Darren Oliver | | 234 | 276 | -42 |
| 2000-05-27 | vs TEX | 50 | W 10-5 | 22-28 | 4 | 13,923 | Joe Mays | Mark Clark | Joe Mays | Mark Clark | | 244 | 281 | -37 |
| 2000-05-28 | vs TEX | 51 | W 4-3 | 23-28 | 4 | 10,033 | Sean Bergman | Rick Helling | Sean Bergman | Rick Helling | LaTroy Hawkins | 248 | 284 | -36 |
| 2000-05-30 | @ TOR | 52 | W 4-1 | 24-28 | 4 | 16,371 | Mark Redman | Kelvim Escobar | Mark Redman | Kelvim Escobar | LaTroy Hawkins | 252 | 285 | -33 |
| 2000-05-31 | @ TOR | 53 | L 2-4 | 24-29 | 4 | 17,305 | Brad Radke | David Wells | David Wells | Brad Radke | Billy Koch | 254 | 289 | -35 |
| 2000-06-01 | @ TOR | 54 | W 5-1 | 25-29 | 4 | 30,444 | Eric Milton | Frank Castillo | Eric Milton | Frank Castillo | | 259 | 290 | -31 |
| 2000-06-02 | @ CIN | 55 | L 3-4 | 25-30 | 4 | 29,269 | Joe Mays | Rob Bell | Rob Bell | Joe Mays | Danny Graves | 262 | 294 | -32 |
| 2000-06-03 | @ CIN | 56 | L 3-9 | 25-31 | 4 | 45,617 | Sean Bergman | Denny Neagle | Denny Neagle | Sean Bergman | | 265 | 303 | -38 |
| 2000-06-04 | @ CIN | 57 | L 2-3 | 25-32 | 4 | 40,169 | Mark Redman | Osvaldo Fernandez | Danny Graves | LaTroy Hawkins | | 267 | 306 | -39 |
| 2000-06-05 | @ HOU | 58 | L 2-8 | 25-33 | 4 | 35,577 | Brad Radke | Scott Elarton | Scott Elarton | Brad Radke | | 269 | 314 | -45 |
| 2000-06-06 | @ HOU | 59 | W 3-1 | 26-33 | 4 | 35,075 | Eric Milton | Jose Lima | Johan Santana | Jose Lima | Eddie Guardado | 272 | 315 | -43 |
| 2000-06-07 | @ HOU | 60 | W 2-0 | 27-33 | 4 | 35,743 | Joe Mays | Shane Reynolds | Joe Mays | Shane Reynolds | Eddie Guardado | 274 | 315 | -41 |
| 2000-06-09 | vs MIL | 61 | W 9-6 | 28-33 | 4 | 20,258 | Sean Bergman | Jamey Wright | Sean Bergman | Jamey Wright | | 283 | 321 | -38 |
| 2000-06-10 | vs MIL | 62 | L 3-5 | 28-34 | 4 | 17,023 | Mark Redman | Jimmy Haynes | Jimmy Haynes | Mark Redman | Bob Wickman | 286 | 326 | -40 |
| 2000-06-11 | vs MIL | 63 | L 3-5 | 28-35 | 4 | 11,715 | Brad Radke | John Snyder | John Snyder | Brad Radke | Bob Wickman | 289 | 331 | -42 |
| 2000-06-12 | vs OAK | 64 | W 7-2 | 29-35 | 4 | 8,486 | Eric Milton | Gil Heredia | Eric Milton | Gil Heredia | | 296 | 333 | -37 |
| 2000-06-13 | vs OAK | 65 | L 5-6 | 29-36 | 4 | 7,485 | Joe Mays | Mark Mulder | Mark Mulder | Joe Mays | Jason Isringhausen | 301 | 339 | -38 |
| 2000-06-14 | vs OAK | 66 | L 6-9 | 29-37 | 4 | 8,911 | Sean Bergman | Tim Hudson | Tim Hudson | Sean Bergman | | 307 | 348 | -41 |
| 2000-06-15 | vs SEA | 67 | L 5-12 | 29-38 | 4 | 9,145 | Mark Redman | Paul Abbott | Robert Ramsay | Mark Redman | | 312 | 360 | -48 |
| 2000-06-16 | vs SEA | 68 | W 7-2 | 30-38 | 4 | 9,636 | Brad Radke | Aaron Sele | Brad Radke | Aaron Sele | | 319 | 362 | -43 |
| 2000-06-17 | vs SEA | 69 | L 3-12 | 30-39 | 4 | 19,404 | Eric Milton | Jamie Moyer | Jamie Moyer | Eric Milton | | 322 | 374 | -52 |
| 2000-06-18 | vs SEA | 70 | L 2-10 | 30-40 | 4 | 11,435 | Joe Mays | Gil Meche | Gil Meche | Joe Mays | | 324 | 384 | -60 |
| 2000-06-20 | @ TEX | 71 | L 2-5 | 30-41 | 4 | 34,608 | Mark Redman | Kenny Rogers | Kenny Rogers | Mark Redman | John Wetteland | 326 | 389 | -63 |
| 2000-06-21 | @ TEX | 72 | L 5-7 | 30-42 | 4 | 28,135 | Brad Radke | Esteban Loaiza | Esteban Loaiza | Brad Radke | John Wetteland | 331 | 396 | -65 |
| 2000-06-22 | @ TEX | 73 | W 3-2 | 31-42 | 4 | 31,320 | Joe Mays | Matt Perisho | LaTroy Hawkins | Tim Crabtree | Bob Wells | 334 | 398 | -64 |
| 2000-06-23 | @ ANA | 74 | L 3-8 | 31-43 | 4 | 30,254 | Jason Ryan | Seth Etherton | Seth Etherton | Jason Ryan | Al Levine | 337 | 406 | -69 |
| 2000-06-24 | @ ANA | 75 | W 11-5 | 32-43 | 4 | 28,917 | Eric Milton | Kent Bottenfield | Eric Milton | Kent Bottenfield | | 348 | 411 | -63 |
| 2000-06-25 | @ ANA | 76 | L 6-7 | 32-44 | 4 | 19,391 | Mark Redman | Brian Cooper | Shigetoshi Hasegawa | Eddie Guardado | | 354 | 418 | -64 |
| 2000-06-26 | @ ANA | 77 | W 10-6 | 33-44 | 4 | 18,768 | Brad Radke | Jarrod Washburn | Brad Radke | Jarrod Washburn | | 364 | 424 | -60 |
| 2000-06-27 | @ CHA | 78 | W 7-4 | 34-44 | 4 | 20,283 | Joe Mays | James Baldwin | Joe Mays | James Baldwin | Bob Wells | 371 | 428 | -57 |
| 2000-06-28 | @ CHA | 79 | L 3-7 | 34-45 | 5 | 17,541 | Mike Lincoln | Cal Eldred | Cal Eldred | Mike Lincoln | | 374 | 435 | -61 |
| 2000-06-29 | @ CHA | 80 | W 10-1 | 35-45 | 4 | 21,239 | Eric Milton | Kip Wells | Eric Milton | Kip Wells | | 384 | 436 | -52 |
| 2000-06-30 | @ CLE | 81 | W 7-2 | 36-45 | 4 | 43,124 | Mark Redman | Jim Brower | Mark Redman | Jim Brower | LaTroy Hawkins | 391 | 438 | -47 |
| 2000-07-01 | @ CLE | 82 | W 4-3 | 37-45 | 4 | 43,185 | Brad Radke | Dave Burba | Eddie Guardado | Steve Karsay | Bob Wells | 395 | 441 | -46 |
| 2000-07-02 | @ CLE | 83 | L 1-7 | 37-46 | 5 | 43,181 | Joe Mays | Chuck Finley | Chuck Finley | Joe Mays | | 396 | 448 | -52 |
| 2000-07-03 | vs BOS | 84 | L 8-11 | 37-47 | 5 | 13,128 | Mike Lincoln | Ramon Martinez | Hipolito Pichardo | Mike Lincoln | Derek Lowe | 404 | 459 | -55 |
| 2000-07-04 | vs BOS | 85 | L 4-14 | 37-48 | 5 | 9,209 | Eric Milton | Tim Wakefield | Tim Wakefield | Eric Milton | Bryce Florie | 408 | 473 | -65 |
| 2000-07-05 | vs BOS | 86 | L 8-11 | 37-49 | 5 | 8,488 | Mark Redman | Jeff Fassero | John Wasdin | Mark Redman | Derek Lowe | 416 | 484 | -68 |
| 2000-07-06 | vs BOS | 87 | L 7-8 | 37-50 | 5 | 10,326 | Brad Radke | Paxton Crawford | Paxton Crawford | Brad Radke | | 423 | 492 | -69 |
| 2000-07-07 | @ PIT | 88 | L 6-8 | 37-51 | 5 | 22,134 | Joe Mays | Todd Ritchie | Jason Christiansen | Bob Wells | Mike Williams | 429 | 500 | -71 |
| 2000-07-08 | @ PIT | 89 | L 1-4 | 37-52 | 5 | 33,814 | Eric Milton | Kris Benson | Kris Benson | Eric Milton | Mike Williams | 430 | 504 | -74 |
| 2000-07-09 | @ PIT | 90 | W 3-2 | 38-52 | 5 | 23,154 | Mark Redman | Jose Silva | Mark Redman | Jose Silva | LaTroy Hawkins | 433 | 506 | -73 |
| 2000-07-13 | vs CHN | 91 | W 5-1 | 39-52 | 5 | 24,161 | Brad Radke | Ismael Valdez | Brad Radke | Ismael Valdez | LaTroy Hawkins | 438 | 507 | -69 |
| 2000-07-14 | vs CHN | 92 | L 2-6 | 39-53 | 5 | 21,429 | Eric Milton | Jon Lieber | Jon Lieber | Eric Milton | | 440 | 513 | -73 |
| 2000-07-15 | vs CHN | 93 | L 4-8 | 39-54 | 5 | 36,688 | Joe Mays | Kevin Tapani | Kevin Tapani | Joe Mays | | 444 | 521 | -77 |
| 2000-07-16 | vs SLN | 94 | W 5-2 | 40-54 | 5 | 30,116 | Mark Redman | Rick Ankiel | Mark Redman | Rick Ankiel | Eddie Guardado | 449 | 523 | -74 |
| 2000-07-17 | vs SLN | 95 | L 3-8 | 40-55 | 5 | 20,171 | Mike Lincoln | Pat Hentgen | Pat Hentgen | Mike Lincoln | | 452 | 531 | -79 |
| 2000-07-18 | vs SLN | 96 | W 3-2 | 41-55 | 5 | 18,115 | Brad Radke | Andy Benes | Brad Radke | Andy Benes | LaTroy Hawkins | 455 | 533 | -78 |
| 2000-07-19 | vs CHA | 97 | L 2-3 | 41-56 | 5 | 12,494 | Eric Milton | Mark Buehrle | Mark Buehrle | Eric Milton | Keith Foulke | 457 | 536 | -79 |
| 2000-07-20 | vs CHA | 98 | W 5-1 | 42-56 | 5 | 18,676 | Joe Mays | Jim Parque | Joe Mays | Jim Parque | | 462 | 537 | -75 |
| 2000-07-21 | vs CLE | 99 | W 2-1 | 43-56 | 5 | 19,231 | Mark Redman | Bartolo Colon | Mark Redman | Bartolo Colon | LaTroy Hawkins | 464 | 538 | -74 |
| 2000-07-22 | vs CLE | 100 | W 10-6 | 44-56 | 5 | 14,108 | Mike Lincoln | Tim Drew | Johan Santana | Kane Davis | Bob Wells | 474 | 544 | -70 |
| 2000-07-23 | vs CLE | 101 | L 3-8 | 44-57 | 5 | 13,623 | Brad Radke | Dave Burba | Dave Burba | Brad Radke | | 477 | 552 | -75 |
| 2000-07-24 | @ BOS | 102 | W 4-2 | 45-57 | 5 | 33,469 | Eric Milton | Tomo Ohka | Eric Milton | Tomo Ohka | | 481 | 554 | -73 |
| 2000-07-25 | @ BOS | 103 | W 4-2 | 46-57 | 5 | 33,668 | Joe Mays | Ramon Martinez | Joe Mays | Ramon Martinez | Eddie Guardado | 485 | 556 | -71 |
| 2000-07-27 | vs NYA | 104 | W 9-3 | 47-57 | 5 | 16,325 | Mark Redman | David Cone | Mark Redman | David Cone | | 494 | 559 | -65 |
| 2000-07-28 | vs NYA | 105 | L 5-9 | 47-58 | 5 | 16,823 | Brad Radke | Denny Neagle | Mariano Rivera | Eddie Guardado | | 499 | 568 | -69 |
| 2000-07-29 | vs NYA | 106 | W 6-2 | 48-58 | 5 | 31,426 | Eric Milton | Roger Clemens | Eric Milton | Ramiro Mendoza | | 505 | 570 | -65 |
| 2000-07-30 | vs NYA | 107 | L 4-7 | 48-59 | 5 | 19,041 | Joe Mays | Andy Pettitte | Andy Pettitte | Joe Mays | | 509 | 577 | -68 |
| 2000-07-31 | @ BAL | 108 | L 5-6 | 48-60 | 5 | 32,661 | J.C. Romero | Sidney Ponson | Sidney Ponson | J.C. Romero | Mike Trombley | 514 | 583 | -69 |
| 2000-08-01 | @ BAL | 109 | L 0-10 | 48-61 | 5 | 35,107 | Mark Redman | Mike Mussina | Mike Mussina | Mark Redman | | 514 | 593 | -79 |
| 2000-08-02 | @ BAL | 110 | W 10-6 | 49-61 | 5 | 37,538 | Brad Radke | Pat Rapp | Brad Radke | Pat Rapp | | 524 | 599 | -75 |
| 2000-08-04 | @ DET | 111 | W 3-1 | 50-61 | 4 | 39,745 | Eric Milton | Willie Blair | Eric Milton | C.J. Nitkowski | Bob Wells | 527 | 600 | -73 |
| 2000-08-05 | @ DET | 112 | L 3-4 | 50-62 | 5 | 39,592 | Joe Mays | Steve Sparks | Steve Sparks | Joe Mays | Todd Jones | 530 | 604 | -74 |
| 2000-08-06 | @ DET | 113 | W 7-3 | 51-62 | 5 | 34,290 | J.C. Romero | Jeff Weaver | J.C. Romero | Jeff Weaver | | 537 | 607 | -70 |
| 2000-08-07 | @ TBA | 114 | W 4-2 | 52-62 | 5 | 14,122 | Mark Redman | Bryan Rekar | Mark Redman | Bryan Rekar | Eddie Guardado | 541 | 609 | -68 |
| 2000-08-08 | @ TBA | 115 | L 0-5 | 52-63 | 5 | 13,155 | Brad Radke | Albie Lopez | Albie Lopez | Brad Radke | | 541 | 614 | -73 |
| 2000-08-09 | @ TBA | 116 | L 4-5 | 52-64 | 5 | 13,916 | Eric Milton | Dave Eiland | Billy Taylor | LaTroy Hawkins | | 545 | 619 | -74 |
| 2000-08-10 | @ TBA | 117 | L 4-10 | 52-65 | 5 | 14,935 | Joe Mays | Tanyon Sturtze | Tanyon Sturtze | Joe Mays | | 549 | 629 | -80 |
| 2000-08-11 | vs TOR | 118 | W 9-4 | 53-65 | 5 | 13,360 | J.C. Romero | Kelvim Escobar | J.C. Romero | Kelvim Escobar | | 558 | 633 | -75 |
| 2000-08-12 | vs TOR | 119 | W 6-3 | 54-65 | 5 | 30,161 | Mark Redman | Esteban Loaiza | Mark Redman | Esteban Loaiza | LaTroy Hawkins | 564 | 636 | -72 |
| 2000-08-13 | vs TOR | 120 | L 3-13 | 54-66 | 5 | 25,656 | Brad Radke | Frank Castillo | Chris Carpenter | Brad Radke | | 567 | 649 | -82 |
| 2000-08-15 | vs KCA | 121 | W 6-2 | 55-66 | 5 | 9,743 | Eric Milton | Jeff Suppan | Eric Milton | Jeff Suppan | Bob Wells | 573 | 651 | -78 |
| 2000-08-16 | vs KCA | 122 | L 3-9 | 55-67 | 5 | 9,617 | J.C. Romero | Brian Meadows | Brian Meadows | J.C. Romero | | 576 | 660 | -84 |
| 2000-08-17 | vs KCA | 123 | L 4-8 | 55-68 | 5 | 16,376 | Mark Redman | Dan Reichert | Dan Reichert | Mark Redman | | 580 | 668 | -88 |
| 2000-08-18 | @ TOR | 124 | L 2-3 | 55-69 | 5 | 23,074 | Matt Kinney | Esteban Loaiza | Esteban Loaiza | Matt Kinney | Billy Koch | 582 | 671 | -89 |
| 2000-08-19 | @ TOR | 125 | W 5-1 | 56-69 | 5 | 25,171 | Brad Radke | Joey Hamilton | Brad Radke | Mark Guthrie | Eddie Guardado | 587 | 672 | -85 |
| 2000-08-20 | @ TOR | 126 | L 3-6 | 56-70 | 5 | 32,627 | Eric Milton | David Wells | David Wells | Hector Carrasco | | 590 | 678 | -88 |
| 2000-08-22 | vs TBA | 127 | L 2-3 | 56-71 | 5 | 7,793 | J.C. Romero | Ryan Rupe | Ryan Rupe | J.C. Romero | Roberto Hernandez | 592 | 681 | -89 |
| 2000-08-23 | vs TBA | 128 | W 8-2 | 57-71 | 5 | 7,278 | Mark Redman | Bryan Rekar | Mark Redman | Bryan Rekar | LaTroy Hawkins | 600 | 683 | -83 |
| 2000-08-25 | vs DET | 129 | W 8-3 | 58-71 | 5 | 8,734 | Brad Radke | Willie Blair | Brad Radke | Willie Blair | Bob Wells | 608 | 686 | -78 |
| 2000-08-26 | vs DET | 130 | L 2-8 | 58-72 | 5 | 12,048 | Eric Milton | Steve Sparks | Steve Sparks | Eric Milton | | 610 | 694 | -84 |
| 2000-08-27 | vs DET | 131 | W 7-6 | 59-72 | 5 | 9,759 | Matt Kinney | Adam Bernero | Hector Carrasco | Todd Jones | | 617 | 700 | -83 |
| 2000-08-29 | @ KCA | 132 | L 3-7 | 59-73 | 5 | 11,931 | J.C. Romero | Blake Stein | Blake Stein | J.C. Romero | | 620 | 707 | -87 |
| 2000-08-30 | @ KCA | 133 | L 7-8 | 59-74 | 5 | 13,273 | Mark Redman | Mac Suzuki | Mac Suzuki | Mark Redman | Ricky Bottalico | 627 | 715 | -88 |
| 2000-09-01 | @ NYA | 134 | L 2-4 | 59-75 | 5 | 38,294 | Brad Radke | Orlando Hernandez | Orlando Hernandez | Brad Radke | Mariano Rivera | 629 | 719 | -90 |
| 2000-09-02 | @ NYA | 135 | L 4-13 | 59-76 | 5 | 47,438 | Eric Milton | Denny Neagle | Denny Neagle | Eric Milton | Jason Grimsley | 633 | 732 | -99 |
| 2000-09-03 | @ NYA | 136 | W 2-1 | 60-76 | 5 | 42,365 | Matt Kinney | Roger Clemens | Eddie Guardado | Mariano Rivera | LaTroy Hawkins | 635 | 733 | -98 |
| 2000-09-04 | vs BAL | 137 | L 2-3 | 60-77 | 5 | 8,373 | Mark Redman | Jose Mercedes | Jose Mercedes | Mark Redman | Ryan Kohlmeier | 637 | 736 | -99 |
| 2000-09-05 | vs BAL | 138 | L 5-6 | 60-78 | 5 | 6,285 | J.C. Romero | Mike Mussina | Mike Mussina | J.C. Romero | Ryan Kohlmeier | 642 | 742 | -100 |
| 2000-09-06 | vs BAL | 139 | W 4-1 | 61-78 | 5 | 5,753 | Brad Radke | Sidney Ponson | Brad Radke | Sidney Ponson | | 646 | 743 | -97 |
| 2000-09-07 | @ BOS | 140 | L 6-11 | 61-79 | 5 | 32,283 | Eric Milton | Ramon Martinez | Ramon Martinez | Eric Milton | | 652 | 754 | -102 |
| 2000-09-08 | @ SEA | 141 | W 4-2 | 62-79 | 5 | 32,081 | Matt Kinney | Paul Abbott | Matt Kinney | Paul Abbott | LaTroy Hawkins | 656 | 756 | -100 |
| 2000-09-09 | @ SEA | 142 | L 2-7 | 62-80 | 5 | 43,249 | Mark Redman | Jamie Moyer | Jamie Moyer | Mark Redman | | 658 | 763 | -105 |
| 2000-09-10 | @ SEA | 143 | L 1-8 | 62-81 | 5 | 39,844 | J.C. Romero | Aaron Sele | Aaron Sele | J.C. Romero | | 659 | 771 | -112 |
| 2000-09-12 | @ OAK | 144 | L 3-5 | 62-82 | 5 | 10,440 | Brad Radke | Mark Mulder | Mark Mulder | Brad Radke | Jason Isringhausen | 662 | 776 | -114 |
| 2000-09-13 | @ OAK | 145 | W 7-6 | 63-82 | 5 | 12,961 | Eric Milton | Gil Heredia | Eric Milton | Gil Heredia | LaTroy Hawkins | 669 | 782 | -113 |
| 2000-09-15 | vs ANA | 146 | L 5-16 | 63-83 | 5 | 10,129 | Matt Kinney | Al Levine | Scott Karl | Matt Kinney | | 674 | 798 | -124 |
| 2000-09-16 | vs ANA | 147 | L 6-7 | 63-84 | 5 | 10,078 | Johan Santana | Scott Schoeneweis | Shigetoshi Hasegawa | LaTroy Hawkins | Troy Percival | 680 | 805 | -125 |
| 2000-09-17 | vs ANA | 148 | W 1-0 | 64-84 | 5 | 7,231 | Brad Radke | Tim Belcher | Brad Radke | Tim Belcher | | 681 | 805 | -124 |
| 2000-09-18 | vs TEX | 149 | W 3-1 | 65-84 | 5 | 7,040 | Joe Mays | Rick Helling | Joe Mays | Rick Helling | Eddie Guardado | 684 | 806 | -122 |
| 2000-09-19 | vs TEX | 150 | W 15-7 | 66-84 | 5 | 6,089 | Matt Kinney | Ryan Glynn | Matt Kinney | Ryan Glynn | | 699 | 813 | -114 |
| 2000-09-20 | vs TEX | 151 | L 4-6 | 66-85 | 5 | 6,072 | J.C. Romero | Doug Davis | John Wetteland | Travis Miller | Mike Venafro | 703 | 819 | -116 |
| 2000-09-21 | vs CHA | 152 | L 4-9 | 66-86 | 5 | 6,688 | Johan Santana | Mike Sirotka | Mike Sirotka | Johan Santana | | 707 | 828 | -121 |
| 2000-09-22 | vs CHA | 153 | L 4-5 | 66-87 | 5 | 9,060 | Brad Radke | Kip Wells | Lorenzo Barcelo | Bob Wells | Keith Foulke | 711 | 833 | -122 |
| 2000-09-23 | vs CHA | 154 | L 3-5 | 66-88 | 5 | 20,263 | Eric Milton | Jim Parque | Jim Parque | Eric Milton | Keith Foulke | 714 | 838 | -124 |
| 2000-09-24 | vs CHA | 155 | W 6-5 | 67-88 | 5 | 9,716 | Joe Mays | Sean Lowe | Eddie Guardado | Kevin Beirne | | 720 | 843 | -123 |
| 2000-09-25 | @ CLE | 156 | W 4-3 | 68-88 | 5 | 42,853 | Matt Kinney | Steve Woodard | Travis Miller | Paul Shuey | LaTroy Hawkins | 724 | 846 | -122 |
| 2000-09-26 | @ CLE | 157 | L 2-4 | 68-89 | 5 | 42,773 | J.C. Romero | Chuck Finley | Chuck Finley | J.C. Romero | Bob Wickman | 726 | 850 | -124 |
| 2000-09-27 | @ CLE | 158 | L 2-8 | 68-90 | 5 | 42,864 | Brad Radke | Jason Bere | Jason Bere | Brad Radke | | 728 | 858 | -130 |
| 2000-09-28 | @ CLE | 159 | W 4-3 | 69-90 | 5 | 42,821 | Eric Milton | Bartolo Colon | Eddie Guardado | Bob Wickman | LaTroy Hawkins | 732 | 861 | -129 |
| 2000-09-29 | @ DET | 160 | L 0-1 | 69-91 | 5 | 28,604 | Joe Mays | Jeff Weaver | Jeff Weaver | Joe Mays | Todd Jones | 732 | 862 | -130 |
| 2000-09-30 | @ DET | 161 | L 5-6 | 69-92 | 5 | 29,321 | Matt Kinney | Steve Sparks | Todd Jones | LaTroy Hawkins | | 737 | 868 | -131 |
| 2000-10-01 | @ DET | 162 | L 11-12 | 69-93 | 5 | 28,293 | J.C. Romero | Brian Moehler | Todd Jones | Eddie Guardado | | 748 | 880 | -132 |