| 2000-04-03 | vs CLE | 1 | L 1-4 | 0-1 | 4 | 46,902 | Mike Mussina | Bartolo Colon | Bartolo Colon | Mike Mussina | Steve Karsay | 1 | 4 | -3 |
| 2000-04-05 | vs CLE | 2 | W 11-7 | 1-1 | 3 | 33,833 | Sidney Ponson | Chuck Finley | B.J. Ryan | Scott Kamieniecki | | 12 | 11 | 1 |
| 2000-04-06 | vs CLE | 3 | W 6-2 | 2-1 | 1 | 35,181 | Pat Rapp | Charles Nagy | Pat Rapp | Charles Nagy | Buddy Groom | 18 | 13 | 5 |
| 2000-04-07 | vs DET | 4 | W 14-10 | 3-1 | 1 | 39,415 | Calvin Maduro | Dave Mlicki | Tim Worrell | Dave Mlicki | | 32 | 23 | 9 |
| 2000-04-08 | vs DET | 5 | W 2-1 | 4-1 | 1 | 42,547 | Mike Mussina | Hideo Nomo | Alberto Reyes | Doug Brocail | | 34 | 24 | 10 |
| 2000-04-09 | vs DET | 6 | W 11-6 | 5-1 | 1 | 42,178 | Jose Mercedes | C.J. Nitkowski | Jose Mercedes | C.J. Nitkowski | | 45 | 30 | 15 |
| 2000-04-11 | @ KCA | 7 | L 5-7 | 5-2 | 1 | 13,080 | Sidney Ponson | Chad Durbin | Jose Santiago | Tim Worrell | | 50 | 37 | 13 |
| 2000-04-12 | @ KCA | 8 | L 6-7 | 5-3 | 1 | 15,228 | Pat Rapp | Mac Suzuki | Jose Santiago | Mike Trombley | | 56 | 44 | 12 |
| 2000-04-13 | @ KCA | 9 | L 5-6 | 5-4 | 2 | 23,724 | Mike Mussina | Jeff Suppan | Ricky Bottalico | B.J. Ryan | | 61 | 50 | 11 |
| 2000-04-14 | @ MIN | 10 | L 9-10 | 5-5 | 2 | 15,249 | Jose Mercedes | Eric Milton | Mark Redman | Buddy Groom | Eddie Guardado | 70 | 60 | 10 |
| 2000-04-15 | @ MIN | 11 | W 6-4 | 6-5 | 2 | 18,745 | Calvin Maduro | Sean Bergman | Tim Worrell | Travis Miller | Mike Trombley | 76 | 64 | 12 |
| 2000-04-16 | @ MIN | 12 | W 5-0 | 7-5 | 2 | 14,066 | Sidney Ponson | Joe Mays | Sidney Ponson | Joe Mays | | 81 | 64 | 17 |
| 2000-04-19 | vs TBA | 13 | W 3-2 | 8-5 | 2 | 40,077 | Mike Mussina | Steve Trachsel | Mike Trombley | Jim Mecir | | 84 | 66 | 18 |
| 2000-04-20 | vs TBA | 14 | W 8-4 | 9-5 | 2 | 34,536 | Pat Rapp | Ryan Rupe | Pat Rapp | Ryan Rupe | | 92 | 70 | 22 |
| 2000-04-21 | @ OAK | 15 | W 11-9 | 10-5 | 2 | 11,802 | Sidney Ponson | Omar Olivares | Sidney Ponson | Omar Olivares | Mike Timlin | 103 | 79 | 24 |
| 2000-04-22 | @ OAK | 16 | W 4-3 | 11-5 | 1 | 23,783 | Jose Mercedes | Gil Heredia | Jose Mercedes | Gil Heredia | Buddy Groom | 107 | 82 | 25 |
| 2000-04-23 | @ OAK | 17 | L 2-3 | 11-6 | 2 | 14,289 | Jason Johnson | Mark Mulder | Jason Isringhausen | Tim Worrell | | 109 | 85 | 24 |
| 2000-04-24 | @ CHA | 18 | L 2-8 | 11-7 | 2 | 15,461 | Mike Mussina | Cal Eldred | Cal Eldred | Mike Mussina | | 111 | 93 | 18 |
| 2000-04-25 | @ CHA | 19 | W 12-6 | 12-7 | 1 | 11,658 | Pat Rapp | Mike Sirotka | Pat Rapp | Mike Sirotka | | 123 | 99 | 24 |
| 2000-04-26 | @ CHA | 20 | L 6-11 | 12-8 | 3 | 13,649 | Sidney Ponson | Kip Wells | Kip Wells | Sidney Ponson | | 129 | 110 | 19 |
| 2000-04-27 | @ CHA | 21 | L 4-13 | 12-9 | 3 | 13,225 | Jose Mercedes | Jim Parque | Jim Parque | Jose Mercedes | | 133 | 123 | 10 |
| 2000-04-28 | vs TEX | 22 | W 4-3 | 13-9 | 2 | 44,092 | Jason Johnson | Esteban Loaiza | Buddy Groom | Jeff Zimmerman | | 137 | 126 | 11 |
| 2000-04-29 | vs TEX | 23 | W 3-1 | 14-9 | 2 | 48,230 | Mike Mussina | Darren Oliver | Mike Mussina | Darren Oliver | | 140 | 127 | 13 |
| 2000-04-30 | vs TEX | 24 | L 4-8 | 14-10 | 2 | 48,563 | Pat Rapp | Kenny Rogers | Kenny Rogers | Pat Rapp | | 144 | 135 | 9 |
| 2000-05-02 | vs ANA | 25 | W 7-6 | 15-10 | 2 | 34,923 | Sidney Ponson | Scott Schoeneweis | Mike Trombley | Troy Percival | | 151 | 141 | 10 |
| 2000-05-03 | vs ANA | 26 | L 5-6 | 15-11 | 3 | 37,961 | Jason Johnson | Ramon Ortiz | Ramon Ortiz | Jason Johnson | Troy Percival | 156 | 147 | 9 |
| 2000-05-04 | vs ANA | 27 | L 5-8 | 15-12 | 3 | 43,892 | Mike Mussina | Ken Hill | Ken Hill | Mike Mussina | Shigetoshi Hasegawa | 161 | 155 | 6 |
| 2000-05-05 | @ NYA | 28 | L 10-12 | 15-13 | 3 | 42,244 | Scott Erickson | Orlando Hernandez | Jeff Nelson | B.J. Ryan | | 171 | 167 | 4 |
| 2000-05-06 | @ NYA | 29 | L 1-3 | 15-14 | 3 | 54,350 | Pat Rapp | Roger Clemens | Roger Clemens | Pat Rapp | Mariano Rivera | 172 | 170 | 2 |
| 2000-05-07 | @ NYA | 30 | W 7-6 | 16-14 | 3 | 52,559 | Sidney Ponson | Ramiro Mendoza | Buddy Groom | Mariano Rivera | Mike Timlin | 179 | 176 | 3 |
| 2000-05-08 | @ TOR | 31 | L 5-6 | 16-15 | 3 | 15,103 | Jason Johnson | Kelvim Escobar | Kelvim Escobar | Jason Johnson | Billy Koch | 184 | 182 | 2 |
| 2000-05-09 | @ TOR | 32 | L 4-6 | 16-16 | 4 | 15,177 | Mike Mussina | David Wells | David Wells | Mike Mussina | Billy Koch | 188 | 188 | 0 |
| 2000-05-10 | @ TOR | 33 | L 2-7 | 16-17 | 4 | 15,598 | Scott Erickson | Lance Painter | Lance Painter | Scott Erickson | Paul Quantrill | 190 | 195 | -5 |
| 2000-05-11 | vs BOS | 34 | L 4-11 | 16-18 | 4 | 43,619 | Pat Rapp | Tim Wakefield | Rheal Cormier | Jose Mercedes | | 194 | 206 | -12 |
| 2000-05-12 | vs BOS | 35 | L 0-9 | 16-19 | 4 | 48,354 | Sidney Ponson | Pedro Martinez | Pedro Martinez | Sidney Ponson | | 194 | 215 | -21 |
| 2000-05-13 | vs BOS | 36 | L 1-5 | 16-20 | 4 | 48,579 | Jason Johnson | Jeff Fassero | Rich Garces | Mike Trombley | | 195 | 220 | -25 |
| 2000-05-14 | vs BOS | 37 | L 1-10 | 16-21 | 4 | 46,107 | Mike Mussina | Brian Rose | Brian Rose | Mike Mussina | | 196 | 230 | -34 |
| 2000-05-16 | @ ANA | 38 | W 4-3 | 17-21 | 4 | 15,881 | Scott Erickson | Kent Bottenfield | Scott Erickson | Kent Bottenfield | Mike Timlin | 200 | 233 | -33 |
| 2000-05-17 | @ ANA | 39 | L 7-8 | 17-22 | 4 | 17,697 | Pat Rapp | Scott Schoeneweis | Troy Percival | Mike Timlin | | 207 | 241 | -34 |
| 2000-05-18 | @ TEX | 40 | L 7-8 | 17-23 | 4 | 32,961 | Sidney Ponson | Rick Helling | Rick Helling | B.J. Ryan | John Wetteland | 214 | 249 | -35 |
| 2000-05-20 | @ TEX | 41 | L 1-2 | 17-24 | 4 | 48,164 | Mike Mussina | Esteban Loaiza | Esteban Loaiza | Mike Mussina | John Wetteland | 215 | 251 | -36 |
| 2000-05-21 | @ TEX | 42 | L 5-6 | 17-25 | 4 | 36,378 | Scott Erickson | Darren Oliver | Mike Venafro | Buddy Groom | John Wetteland | 220 | 257 | -37 |
| 2000-05-23 | vs SEA | 43 | W 4-2 | 18-25 | 4 | 37,747 | Pat Rapp | Gil Meche | Mike Timlin | Jose Mesa | | 224 | 259 | -35 |
| 2000-05-24 | vs SEA | 44 | W 4-3 | 19-25 | 4 | 37,262 | Sidney Ponson | John Halama | Buddy Groom | Kazuhiro Sasaki | | 228 | 262 | -34 |
| 2000-05-25 | vs SEA | 45 | W 5-1 | 20-25 | 4 | 34,764 | Mike Mussina | Paul Abbott | Mike Mussina | Frankie Rodriguez | | 233 | 263 | -30 |
| 2000-05-26 | vs OAK | 46 | W 8-3 | 21-25 | 4 | 36,708 | Scott Erickson | Mark Mulder | Scott Erickson | Mark Mulder | | 241 | 266 | -25 |
| 2000-05-27 | vs OAK | 47 | L 0-4 | 21-26 | 4 | 38,656 | Jason Johnson | Tim Hudson | Tim Hudson | Jason Johnson | | 241 | 270 | -29 |
| 2000-05-29 | @ TBA | 48 | W 5-1 | 22-26 | 4 | 24,209 | Pat Rapp | Steve Trachsel | Pat Rapp | Steve Trachsel | | 246 | 271 | -25 |
| 2000-05-30 | @ TBA | 49 | W 8-7 | 23-26 | 4 | 13,113 | Sidney Ponson | Esteban Yan | Sidney Ponson | Esteban Yan | Mike Timlin | 254 | 278 | -24 |
| 2000-05-31 | @ TBA | 50 | L 3-4 | 23-27 | 4 | 13,870 | Mike Mussina | Cory Lidle | Jim Mecir | Buddy Groom | Roberto Hernandez | 257 | 282 | -25 |
| 2000-06-01 | @ TBA | 51 | L 1-2 | 23-28 | 4 | 14,108 | Scott Erickson | Bryan Rekar | Bryan Rekar | Scott Erickson | Roberto Hernandez | 258 | 284 | -26 |
| 2000-06-02 | @ MON | 52 | L 3-5 | 23-29 | 4 | 12,654 | Jason Johnson | Carl Pavano | Carl Pavano | Jason Johnson | Steve Kline | 261 | 289 | -28 |
| 2000-06-03 | @ MON | 53 | L 4-7 | 23-30 | 4 | 13,628 | Pat Rapp | T.J. Tucker | Felipe Lira | Pat Rapp | Steve Kline | 265 | 296 | -31 |
| 2000-06-04 | @ MON | 54 | L 0-1 | 23-31 | 4 | 15,181 | Sidney Ponson | Tony Armas | Tony Armas | Sidney Ponson | Steve Kline | 265 | 297 | -32 |
| 2000-06-05 | @ NYN | 55 | W 4-2 | 24-31 | 4 | 25,192 | Mike Mussina | Mike Hampton | Mike Mussina | Mike Hampton | Mike Timlin | 269 | 299 | -30 |
| 2000-06-07 | @ NYN | 56 | L 3-11 | 24-32 | 4 | 34,492 | Scott Erickson | Rick Reed | Pat Mahomes | Scott Erickson | | 272 | 310 | -38 |
| 2000-06-08 | @ NYN | 57 | L 7-8 | 24-33 | 4 | 9,540 | Jason Johnson | Glendon Rusch | Dennis Cook | Jose Mercedes | | 279 | 318 | -39 |
| 2000-06-09 | vs PHI | 58 | L 5-9 | 24-34 | 4 | 47,218 | Pat Rapp | Randy Wolf | Randy Wolf | Pat Rapp | | 284 | 327 | -43 |
| 2000-06-10 | vs PHI | 59 | W 11-4 | 25-34 | 4 | 48,443 | Sidney Ponson | Curt Schilling | Sidney Ponson | Curt Schilling | | 295 | 331 | -36 |
| 2000-06-11 | vs PHI | 60 | W 7-2 | 26-34 | 4 | 47,540 | Mike Mussina | Andy Ashby | Mike Mussina | Andy Ashby | | 302 | 333 | -31 |
| 2000-06-13 | vs TEX | 61 | W 3-2 | 27-34 | 4 | 40,175 | Scott Erickson | Rick Helling | Scott Erickson | Rick Helling | Mike Timlin | 305 | 335 | -30 |
| 2000-06-14 | vs TEX | 62 | W 11-10 | 28-34 | 4 | 39,231 | Pat Rapp | Kenny Rogers | Mike Timlin | Tim Crabtree | | 316 | 345 | -29 |
| 2000-06-15 | vs TEX | 63 | W 10-1 | 29-34 | 4 | 46,884 | Sidney Ponson | Esteban Loaiza | Chuck McElroy | Esteban Loaiza | | 326 | 346 | -20 |
| 2000-06-16 | vs ANA | 64 | W 4-3 | 30-34 | 4 | 45,006 | Mike Mussina | Scott Schoeneweis | Mike Mussina | Scott Schoeneweis | Mike Timlin | 330 | 349 | -19 |
| 2000-06-17 | vs ANA | 65 | L 3-8 | 30-35 | 4 | 45,758 | Jason Johnson | Tim Belcher | Tim Belcher | Jason Johnson | | 333 | 357 | -24 |
| 2000-06-18 | vs ANA | 66 | L 6-8 | 30-36 | 4 | 41,198 | Scott Erickson | Seth Etherton | Seth Etherton | Scott Erickson | Troy Percival | 339 | 365 | -26 |
| 2000-06-19 | @ OAK | 67 | L 12-13 | 30-37 | 4 | 13,297 | Pat Rapp | Mark Mulder | Jeff Tam | Mike Timlin | | 351 | 378 | -27 |
| 2000-06-20 | @ OAK | 68 | L 5-8 | 30-38 | 4 | 20,337 | Sidney Ponson | Tim Hudson | Tim Hudson | Sidney Ponson | Jason Isringhausen | 356 | 386 | -30 |
| 2000-06-21 | @ OAK | 69 | L 3-10 | 30-39 | 4 | 25,287 | Mike Mussina | Ariel Prieto | Ariel Prieto | Mike Mussina | | 359 | 396 | -37 |
| 2000-06-22 | @ SEA | 70 | L 4-11 | 30-40 | 4 | 31,688 | Jason Johnson | Jamie Moyer | Jamie Moyer | Jason Johnson | | 363 | 407 | -44 |
| 2000-06-23 | @ SEA | 71 | L 3-8 | 30-41 | 4 | 40,383 | Scott Erickson | Gil Meche | Gil Meche | Scott Erickson | | 366 | 415 | -49 |
| 2000-06-24 | @ SEA | 72 | L 1-2 | 30-42 | 4 | 45,142 | Pat Rapp | John Halama | John Halama | Pat Rapp | Kazuhiro Sasaki | 367 | 417 | -50 |
| 2000-06-25 | @ SEA | 73 | L 2-4 | 30-43 | 4 | 45,030 | Sidney Ponson | Paul Abbott | Arthur Rhodes | Mike Timlin | Kazuhiro Sasaki | 369 | 421 | -52 |
| 2000-06-27 | @ BOS | 74 | W 6-3 | 31-43 | 4 | 32,813 | Mike Mussina | Pete Schourek | Mike Trombley | Derek Lowe | Buddy Groom | 375 | 424 | -49 |
| 2000-06-28 | @ BOS | 75 | W 8-7 | 32-43 | 4 | 33,834 | Jason Johnson | Ramon Martinez | Jose Mercedes | Bryce Florie | Buddy Groom | 383 | 431 | -48 |
| 2000-06-29 | @ BOS | 76 | L 4-12 | 32-44 | 4 | 33,612 | Scott Erickson | Tim Wakefield | Tim Wakefield | Scott Erickson | | 387 | 443 | -56 |
| 2000-06-30 | vs TOR | 77 | W 8-3 | 33-44 | 4 | 40,412 | Pat Rapp | Roy Halladay | Pat Rapp | Roy Halladay | | 395 | 446 | -51 |
| 2000-07-01 | vs TOR | 78 | W 12-5 | 34-44 | 4 | 40,876 | Sidney Ponson | Chris Carpenter | Sidney Ponson | Chris Carpenter | | 407 | 451 | -44 |
| 2000-07-02 | vs TOR | 79 | W 3-2 | 35-44 | 4 | 41,267 | Mike Mussina | Kelvim Escobar | Mike Trombley | Paul Quantrill | Alan Mills | 410 | 453 | -43 |
| 2000-07-03 | vs TOR | 80 | L 4-6 | 35-45 | 4 | 39,617 | Jason Johnson | David Wells | David Wells | Jason Johnson | Billy Koch | 414 | 459 | -45 |
| 2000-07-04 | @ NYA | 81 | W 7-6 | 36-45 | 4 | 44,447 | Scott Erickson | David Cone | Scott Erickson | David Cone | Mike Trombley | 421 | 465 | -44 |
| 2000-07-05 | @ NYA | 82 | L 6-12 | 36-46 | 4 | 40,031 | Pat Rapp | Andy Pettitte | Andy Pettitte | Pat Rapp | | 427 | 477 | -50 |
| 2000-07-06 | @ NYA | 83 | L 9-13 | 36-47 | 4 | 44,104 | Sidney Ponson | Ed Yarnall | Mike Stanton | Jason Johnson | | 436 | 490 | -54 |
| 2000-07-07 | @ PHI | 84 | W 2-1 | 37-47 | 4 | 21,882 | Mike Mussina | Curt Schilling | Mike Mussina | Curt Schilling | Mike Timlin | 438 | 491 | -53 |
| 2000-07-08 | @ PHI | 85 | L 4-13 | 37-48 | 4 | 28,385 | Jose Mercedes | Andy Ashby | Andy Ashby | Jose Mercedes | | 442 | 504 | -62 |
| 2000-07-09 | @ PHI | 86 | W 5-4 | 38-48 | 4 | 28,100 | Scott Erickson | Dave Coggin | Alan Mills | Jeff Brantley | Mike Timlin | 447 | 508 | -61 |
| 2000-07-13 | vs ATL | 87 | L 3-6 | 38-49 | 4 | 47,284 | Mike Mussina | Greg Maddux | Greg Maddux | Mike Mussina | Scott Kamieniecki | 450 | 514 | -64 |
| 2000-07-14 | vs ATL | 88 | L 1-4 | 38-50 | 4 | 47,715 | Sidney Ponson | Andy Ashby | Andy Ashby | Sidney Ponson | | 451 | 518 | -67 |
| 2000-07-15 | vs ATL | 89 | L 3-7 | 38-51 | 4 | 49,013 | Scott Erickson | Tom Glavine | Tom Glavine | Scott Erickson | | 454 | 525 | -71 |
| 2000-07-16 | vs FLO | 90 | W 9-5 | 39-51 | 4 | 42,444 | Pat Rapp | Chuck Smith | Alan Mills | Vic Darensbourg | Mike Timlin | 463 | 530 | -67 |
| 2000-07-17 | vs FLO | 91 | W 5-3 | 40-51 | 4 | 37,591 | Jose Mercedes | Reid Cornelius | Jose Mercedes | Reid Cornelius | Mike Timlin | 468 | 533 | -65 |
| 2000-07-18 | vs FLO | 92 | L 0-7 | 40-52 | 4 | 38,828 | Mike Mussina | Jesus Sanchez | Jesus Sanchez | Mike Mussina | | 468 | 540 | -72 |
| 2000-07-20 | vs BOS | 93 | L 7-11 | 41-53 | 4 | 42,048 | Sidney Ponson | Ramon Martinez | Ramon Martinez | Sidney Ponson | | 475 | 551 | -76 |
| 2000-07-20 | vs BOS | 94 | W 9-4 | 41-53 | 4 | 46,167 | Scott Erickson | Pete Schourek | Scott Erickson | Pete Schourek | | 484 | 555 | -71 |
| 2000-07-21 | @ TOR | 95 | W 9-5 | 42-53 | 4 | 23,470 | Pat Rapp | Roy Halladay | Pat Rapp | Roy Halladay | | 493 | 560 | -67 |
| 2000-07-22 | @ TOR | 96 | W 8-2 | 43-53 | 4 | 27,585 | Jose Mercedes | Esteban Loaiza | Jose Mercedes | Esteban Loaiza | | 501 | 562 | -61 |
| 2000-07-23 | @ TOR | 97 | L 1-4 | 43-54 | 4 | 26,276 | Mike Mussina | Frank Castillo | Frank Castillo | Mike Mussina | Billy Koch | 502 | 566 | -64 |
| 2000-07-24 | vs NYA | 98 | L 3-4 | 43-55 | 4 | 47,450 | John Parrish | Roger Clemens | Roger Clemens | John Parrish | Mariano Rivera | 505 | 570 | -65 |
| 2000-07-25 | vs NYA | 99 | L 1-19 | 43-56 | 4 | 47,874 | Scott Erickson | Andy Pettitte | Andy Pettitte | Scott Erickson | | 506 | 589 | -83 |
| 2000-07-26 | vs NYA | 100 | L 1-4 | 43-57 | 4 | 47,691 | Sidney Ponson | Dwight Gooden | Dwight Gooden | Sidney Ponson | Mariano Rivera | 507 | 593 | -86 |
| 2000-07-29 | vs CLE | 101 | L 3-14 | 44-58 | 4 | 47,715 | Pat Rapp | Jason Bere | Jason Bere | Pat Rapp | | 510 | 607 | -97 |
| 2000-07-29 | vs CLE | 102 | W 4-0 | 44-58 | 4 | 47,355 | Jose Mercedes | Steve Woodard | Jose Mercedes | Steve Woodard | | 514 | 607 | -93 |
| 2000-07-30 | vs CLE | 103 | W 10-7 | 45-58 | 4 | 47,065 | John Parrish | Chuck Finley | John Parrish | Chuck Finley | | 524 | 614 | -90 |
| 2000-07-31 | vs MIN | 104 | W 6-5 | 46-58 | 4 | 32,661 | Sidney Ponson | J.C. Romero | Sidney Ponson | J.C. Romero | Mike Trombley | 530 | 619 | -89 |
| 2000-08-01 | vs MIN | 105 | W 10-0 | 47-58 | 4 | 35,107 | Mike Mussina | Mark Redman | Mike Mussina | Mark Redman | | 540 | 619 | -79 |
| 2000-08-02 | vs MIN | 106 | L 6-10 | 47-59 | 4 | 37,538 | Pat Rapp | Brad Radke | Brad Radke | Pat Rapp | | 546 | 629 | -83 |
| 2000-08-04 | @ TBA | 107 | W 10-9 | 48-59 | 4 | 15,590 | Jose Mercedes | Travis Harper | Jason Johnson | Esteban Yan | | 556 | 638 | -82 |
| 2000-08-05 | @ TBA | 108 | L 4-5 | 48-60 | 4 | 18,471 | Sidney Ponson | Tanyon Sturtze | Roberto Hernandez | Mike Trombley | | 560 | 643 | -83 |
| 2000-08-06 | @ TBA | 109 | L 4-7 | 48-61 | 4 | 18,864 | Mike Mussina | Ryan Rupe | Ryan Rupe | Mike Mussina | Roberto Hernandez | 564 | 650 | -86 |
| 2000-08-07 | @ DET | 110 | W 4-3 | 49-61 | 4 | 27,392 | John Parrish | Adam Bernero | Buddy Groom | Doug Brocail | Ryan Kohlmeier | 568 | 653 | -85 |
| 2000-08-08 | @ DET | 111 | L 1-4 | 49-62 | 4 | 30,190 | Pat Rapp | Brian Moehler | Brian Moehler | Pat Rapp | | 569 | 657 | -88 |
| 2000-08-09 | @ DET | 112 | W 5-2 | 50-62 | 4 | 28,041 | Jose Mercedes | Willie Blair | Jose Mercedes | Willie Blair | Ryan Kohlmeier | 574 | 659 | -85 |
| 2000-08-10 | @ DET | 113 | L 3-14 | 50-63 | 4 | 40,093 | Sidney Ponson | Steve Sparks | Steve Sparks | Sidney Ponson | | 577 | 673 | -96 |
| 2000-08-11 | @ KCA | 114 | L 6-7 | 50-64 | 4 | 20,940 | Mike Mussina | Dan Reichert | Dan Reichert | Mike Mussina | Ricky Bottalico | 583 | 680 | -97 |
| 2000-08-12 | @ KCA | 115 | W 12-11 | 51-64 | 4 | 36,658 | John Parrish | Blake Stein | Buddy Groom | Ricky Bottalico | Ryan Kohlmeier | 595 | 691 | -96 |
| 2000-08-13 | @ KCA | 116 | L 5-10 | 51-65 | 4 | 16,702 | Leslie Brea | Mac Suzuki | Mac Suzuki | Leslie Brea | | 600 | 701 | -101 |
| 2000-08-14 | vs CHA | 117 | W 8-2 | 52-65 | 4 | 40,047 | Jose Mercedes | Mike Sirotka | Jose Mercedes | Mike Sirotka | | 608 | 703 | -95 |
| 2000-08-15 | vs CHA | 118 | L 4-14 | 52-66 | 4 | 37,707 | Jason Johnson | Rocky Biddle | Rocky Biddle | Jason Johnson | | 612 | 717 | -105 |
| 2000-08-16 | vs CHA | 119 | L 3-7 | 52-67 | 4 | 39,079 | Mike Mussina | Jim Parque | Jim Parque | Mike Mussina | | 615 | 724 | -109 |
| 2000-08-17 | vs CHA | 120 | W 5-3 | 53-67 | 4 | 40,205 | John Parrish | James Baldwin | John Parrish | James Baldwin | | 620 | 727 | -107 |
| 2000-08-18 | vs KCA | 121 | L 1-4 | 53-68 | 4 | 40,265 | Pat Rapp | Blake Stein | Blake Stein | Pat Rapp | | 621 | 731 | -110 |
| 2000-08-19 | vs KCA | 122 | L 0-7 | 53-69 | 4 | 43,827 | Jose Mercedes | Mac Suzuki | Mac Suzuki | Jose Mercedes | | 621 | 738 | -117 |
| 2000-08-20 | vs KCA | 123 | W 2-1 | 54-69 | 4 | 38,753 | Sidney Ponson | Jeff Suppan | Sidney Ponson | Kris Wilson | Ryan Kohlmeier | 623 | 739 | -116 |
| 2000-08-21 | vs KCA | 124 | W 2-1 | 55-69 | 4 | 33,365 | Mike Mussina | Brian Meadows | Mike Mussina | Brian Meadows | Ryan Kohlmeier | 625 | 740 | -115 |
| 2000-08-23 | @ CHA | 125 | L 4-8 | 55-70 | 4 | 22,528 | John Parrish | Sean Lowe | Lorenzo Barcelo | John Parrish | | 629 | 748 | -119 |
| 2000-08-24 | @ CHA | 126 | W 8-5 | 56-70 | 4 | 20,007 | Jose Mercedes | Ken Hill | Jose Mercedes | Ken Hill | | 637 | 753 | -116 |
| 2000-08-25 | vs TBA | 127 | W 4-3 | 57-70 | 4 | 34,503 | Pat Rapp | Albie Lopez | B.J. Ryan | Billy Taylor | Ryan Kohlmeier | 641 | 756 | -115 |
| 2000-08-26 | vs TBA | 128 | L 1-4 | 58-71 | 4 | 40,441 | Sidney Ponson | Tanyon Sturtze | Dave Eiland | Sidney Ponson | Roberto Hernandez | 642 | 760 | -118 |
| 2000-08-26 | vs TBA | 129 | W 2-0 | 58-71 | 4 | 38,783 | Mike Mussina | Paul Wilson | Buddy Groom | Cory Lidle | Mike Trombley | 644 | 760 | -116 |
| 2000-08-27 | vs TBA | 130 | W 3-2 | 59-71 | 4 | 36,078 | Jay Spurgeon | Ryan Rupe | Jay Spurgeon | Ryan Rupe | Ryan Kohlmeier | 647 | 762 | -115 |
| 2000-08-29 | vs DET | 131 | L 2-12 | 59-72 | 4 | 31,980 | John Parrish | Jeff Weaver | Jeff Weaver | John Parrish | | 649 | 774 | -125 |
| 2000-08-30 | vs DET | 132 | W 5-1 | 60-72 | 4 | 31,383 | Jose Mercedes | Hideo Nomo | Jose Mercedes | Hideo Nomo | | 654 | 775 | -121 |
| 2000-08-31 | vs DET | 133 | L 1-6 | 60-73 | 4 | 33,709 | Mike Mussina | Brian Moehler | Danny Patterson | Mike Trombley | | 655 | 781 | -126 |
| 2000-09-01 | @ CLE | 134 | L 2-5 | 60-74 | 4 | 42,647 | Sidney Ponson | Chuck Finley | Chuck Finley | Sidney Ponson | Bob Wickman | 657 | 786 | -129 |
| 2000-09-02 | @ CLE | 135 | W 8-6 | 61-74 | 4 | 42,736 | Pat Rapp | Bartolo Colon | Pat Rapp | Steve Karsay | Ryan Kohlmeier | 665 | 792 | -127 |
| 2000-09-03 | @ CLE | 136 | L 11-12 | 61-75 | 4 | 42,630 | Jay Spurgeon | Steve Woodard | Cameron Cairncross | Mike Trombley | | 676 | 804 | -128 |
| 2000-09-04 | @ MIN | 137 | W 3-2 | 62-75 | 4 | 8,373 | Jose Mercedes | Mark Redman | Jose Mercedes | Mark Redman | Ryan Kohlmeier | 679 | 806 | -127 |
| 2000-09-05 | @ MIN | 138 | W 6-5 | 63-75 | 4 | 6,285 | Mike Mussina | J.C. Romero | Mike Mussina | J.C. Romero | Ryan Kohlmeier | 685 | 811 | -126 |
| 2000-09-06 | @ MIN | 139 | L 1-4 | 63-76 | 4 | 5,753 | Sidney Ponson | Brad Radke | Brad Radke | Sidney Ponson | | 686 | 815 | -129 |
| 2000-09-08 | @ ANA | 140 | L 1-2 | 63-77 | 4 | 30,480 | Pat Rapp | Ramon Ortiz | Ramon Ortiz | Pat Rapp | Troy Percival | 687 | 817 | -130 |
| 2000-09-09 | @ ANA | 141 | W 10-3 | 64-77 | 4 | 22,332 | Jose Mercedes | Scott Karl | Jose Mercedes | Scott Karl | | 697 | 820 | -123 |
| 2000-09-10 | @ ANA | 142 | L 1-2 | 64-78 | 4 | 22,606 | Mike Mussina | Al Levine | Shigetoshi Hasegawa | Mike Mussina | Troy Percival | 698 | 822 | -124 |
| 2000-09-11 | @ ANA | 143 | W 3-1 | 65-78 | 4 | 17,323 | Sidney Ponson | Scott Schoeneweis | Sidney Ponson | Scott Schoeneweis | | 701 | 823 | -122 |
| 2000-09-12 | @ TEX | 144 | L 1-9 | 65-80 | 4 | 0 | John Parrish | Rick Helling | Rick Helling | John Parrish | | 702 | 832 | -130 |
| 2000-09-12 | @ TEX | 145 | L 5-6 | 65-80 | 4 | 24,221 | Jay Spurgeon | Kenny Rogers | Kenny Rogers | Jay Spurgeon | John Wetteland | 707 | 838 | -131 |
| 2000-09-13 | @ TEX | 146 | W 9-4 | 66-80 | 4 | 24,819 | Pat Rapp | Ryan Glynn | Pat Rapp | Ryan Glynn | | 716 | 842 | -126 |
| 2000-09-15 | vs SEA | 147 | L 2-10 | 66-81 | 4 | 38,510 | Jose Mercedes | Aaron Sele | Aaron Sele | Jose Mercedes | | 718 | 852 | -134 |
| 2000-09-16 | vs SEA | 148 | L 0-14 | 66-82 | 4 | 44,619 | Mike Mussina | Jamie Moyer | Jamie Moyer | Mike Mussina | | 718 | 866 | -148 |
| 2000-09-17 | vs SEA | 149 | L 2-3 | 66-83 | 4 | 40,440 | Sidney Ponson | Freddy Garcia | Freddy Garcia | Sidney Ponson | Kazuhiro Sasaki | 720 | 869 | -149 |
| 2000-09-18 | vs OAK | 150 | L 3-12 | 66-84 | 4 | 30,341 | Pat Rapp | Kevin Appier | Kevin Appier | Pat Rapp | | 723 | 881 | -158 |
| 2000-09-19 | vs OAK | 151 | L 4-7 | 66-85 | 4 | 30,166 | Jay Spurgeon | Ariel Prieto | Jim Mecir | Jason Johnson | Jason Isringhausen | 727 | 888 | -161 |
| 2000-09-20 | vs OAK | 152 | W 2-0 | 67-86 | 4 | 32,539 | Chuck McElroy | Barry Zito | Chuck McElroy | Barry Zito | Ryan Kohlmeier | 729 | 888 | -159 |
| 2000-09-20 | vs OAK | 153 | L 0-4 | 67-86 | 4 | 33,181 | Jose Mercedes | Gil Heredia | Gil Heredia | Jose Mercedes | | 729 | 892 | -163 |
| 2000-09-22 | @ BOS | 154 | W 3-1 | 68-86 | 4 | 32,708 | Sidney Ponson | Ramon Martinez | Sidney Ponson | Ramon Martinez | | 732 | 893 | -161 |
| 2000-09-23 | @ BOS | 155 | L 7-8 | 68-87 | 4 | 32,273 | Pat Rapp | Rolando Arrojo | Hector Carrasco | Ryan Kohlmeier | | 739 | 901 | -162 |
| 2000-09-24 | @ BOS | 156 | W 1-0 | 69-87 | 4 | 32,183 | Mike Mussina | Tomo Ohka | Mike Mussina | Tomo Ohka | Ryan Kohlmeier | 740 | 901 | -161 |
| 2000-09-26 | vs TOR | 157 | W 2-1 | 70-87 | 4 | 31,614 | Jose Mercedes | David Wells | Jose Mercedes | David Wells | Ryan Kohlmeier | 742 | 902 | -160 |
| 2000-09-27 | vs TOR | 158 | L 0-4 | 70-88 | 4 | 30,362 | Sidney Ponson | Frank Castillo | Frank Castillo | Sidney Ponson | | 742 | 906 | -164 |
| 2000-09-28 | vs TOR | 159 | W 23-1 | 71-88 | 4 | 32,203 | Pat Rapp | Chris Carpenter | Pat Rapp | Chris Carpenter | | 765 | 907 | -142 |
| 2000-09-29 | vs NYA | 160 | W 13-2 | 72-88 | 4 | 47,674 | Chuck McElroy | Andy Pettitte | Chuck McElroy | Andy Pettitte | | 778 | 909 | -131 |
| 2000-09-30 | vs NYA | 161 | W 9-1 | 73-88 | 4 | 48,129 | Mike Mussina | David Cone | Mike Mussina | David Cone | | 787 | 910 | -123 |
| 2000-10-01 | vs NYA | 162 | W 7-3 | 74-88 | 4 | 47,831 | Jose Mercedes | Orlando Hernandez | Jose Mercedes | Orlando Hernandez | | 794 | 913 | -119 |