| 2000-04-03 | vs CHA | 1 | W 10-4 | 1-0 | 1 | 49,332 | Kenny Rogers | Mike Sirotka | Kenny Rogers | Mike Sirotka | | 10 | 4 | 6 |
| 2000-04-04 | vs CHA | 2 | W 12-8 | 2-0 | 1 | 29,418 | Rick Helling | Kip Wells | Francisco Cordero | Bill Simas | | 22 | 12 | 10 |
| 2000-04-05 | vs CHA | 3 | L 8-12 | 2-1 | 2 | 25,544 | Darren Oliver | Jim Parque | Keith Foulke | Jeff Zimmerman | | 30 | 24 | 6 |
| 2000-04-06 | vs CHA | 4 | L 2-6 | 2-2 | 3 | 28,466 | Esteban Loaiza | James Baldwin | James Baldwin | Esteban Loaiza | | 32 | 30 | 2 |
| 2000-04-07 | vs TOR | 5 | W 11-5 | 3-2 | 2 | 31,619 | Mark Clark | Frank Castillo | Mark Clark | Frank Castillo | | 43 | 35 | 8 |
| 2000-04-08 | vs TOR | 6 | L 0-4 | 3-3 | 3 | 37,128 | Kenny Rogers | David Wells | David Wells | Kenny Rogers | | 43 | 39 | 4 |
| 2000-04-09 | vs TOR | 7 | W 7-5 | 4-3 | 2 | 40,186 | Rick Helling | Roy Halladay | Rick Helling | Roy Halladay | | 50 | 44 | 6 |
| 2000-04-12 | @ NYA | 8 | L 6-8 | 4-4 | 3 | 48,487 | Darren Oliver | David Cone | Jeff Nelson | Mike Munoz | Mariano Rivera | 56 | 52 | 4 |
| 2000-04-13 | @ NYA | 9 | L 1-5 | 4-5 | 3 | 23,805 | Kenny Rogers | Orlando Hernandez | Orlando Hernandez | Kenny Rogers | | 57 | 57 | 0 |
| 2000-04-14 | @ CLE | 10 | W 7-2 | 5-5 | 3 | 42,727 | Rick Helling | Dave Burba | Rick Helling | Dave Burba | | 64 | 59 | 5 |
| 2000-04-15 | @ CLE | 11 | W 6-4 | 6-5 | 3 | 40,543 | Mark Clark | Bartolo Colon | Mark Clark | Bartolo Colon | John Wetteland | 70 | 63 | 7 |
| 2000-04-16 | @ CLE | 12 | L 1-2 | 6-6 | 3 | 40,626 | Esteban Loaiza | Chuck Finley | Chuck Finley | John Wetteland | | 71 | 65 | 6 |
| 2000-04-17 | vs NYA | 13 | L 4-5 | 6-7 | 3 | 38,166 | Darren Oliver | David Cone | Mariano Rivera | Tim Crabtree | Todd Erdos | 75 | 70 | 5 |
| 2000-04-18 | vs NYA | 14 | L 3-6 | 6-8 | 4 | 43,644 | Kenny Rogers | Orlando Hernandez | Orlando Hernandez | Kenny Rogers | | 78 | 76 | 2 |
| 2000-04-19 | vs NYA | 15 | L 4-5 | 6-9 | 4 | 39,294 | Rick Helling | Roger Clemens | Mariano Rivera | Jeff Zimmerman | | 82 | 81 | 1 |
| 2000-04-21 | vs MIN | 16 | L 5-10 | 6-10 | 4 | 35,155 | Mark Clark | Joe Mays | Hector Carrasco | Mark Clark | | 87 | 91 | -4 |
| 2000-04-22 | vs MIN | 17 | W 8-3 | 7-10 | 3 | 42,659 | Esteban Loaiza | Johan Santana | Esteban Loaiza | Johan Santana | | 95 | 94 | 1 |
| 2000-04-23 | vs MIN | 18 | L 4-5 | 7-11 | 4 | 30,081 | Darren Oliver | Brad Radke | Brad Radke | Darren Oliver | Bob Wells | 99 | 99 | 0 |
| 2000-04-24 | vs BOS | 19 | W 5-4 | 8-11 | 3 | 26,940 | Kenny Rogers | Ramon Martinez | Kenny Rogers | Tim Wakefield | John Wetteland | 104 | 103 | 1 |
| 2000-04-25 | vs BOS | 20 | L 3-6 | 8-12 | 4 | 31,692 | Rick Helling | Pedro Martinez | Pedro Martinez | Rick Helling | Derek Lowe | 107 | 109 | -2 |
| 2000-04-26 | vs BOS | 21 | L 4-14 | 8-13 | 4 | 28,698 | Mark Clark | Jeff Fassero | Jeff Fassero | Mark Clark | | 111 | 123 | -12 |
| 2000-04-28 | @ BAL | 22 | L 3-4 | 8-14 | 4 | 44,092 | Esteban Loaiza | Jason Johnson | Buddy Groom | Jeff Zimmerman | | 114 | 127 | -13 |
| 2000-04-29 | @ BAL | 23 | L 1-3 | 8-15 | 4 | 48,230 | Darren Oliver | Mike Mussina | Mike Mussina | Darren Oliver | | 115 | 130 | -15 |
| 2000-04-30 | @ BAL | 24 | W 8-4 | 9-15 | 4 | 48,563 | Kenny Rogers | Pat Rapp | Kenny Rogers | Pat Rapp | | 123 | 134 | -11 |
| 2000-05-02 | @ TBA | 25 | W 8-1 | 10-15 | 4 | 15,067 | Rick Helling | Ryan Rupe | Rick Helling | Ryan Rupe | | 131 | 135 | -4 |
| 2000-05-03 | @ TBA | 26 | W 5-1 | 11-15 | 4 | 14,064 | Mark Clark | Dwight Gooden | Mark Clark | Dwight Gooden | John Wetteland | 136 | 136 | 0 |
| 2000-05-04 | @ TBA | 27 | L 7-8 | 11-16 | 4 | 14,107 | Esteban Loaiza | Esteban Yan | Albie Lopez | Jeff Zimmerman | | 143 | 144 | -1 |
| 2000-05-05 | vs OAK | 28 | W 17-16 | 12-16 | 4 | 38,949 | Darren Oliver | Mark Mulder | John Wetteland | Jeff Tam | | 160 | 160 | 0 |
| 2000-05-06 | vs OAK | 29 | W 11-10 | 13-16 | 4 | 47,627 | Kenny Rogers | Tim Hudson | John Wetteland | Jason Isringhausen | | 171 | 170 | 1 |
| 2000-05-07 | vs OAK | 30 | L 6-7 | 13-17 | 4 | 39,368 | Doug Davis | Omar Olivares | Omar Olivares | Doug Davis | Doug Jones | 177 | 177 | 0 |
| 2000-05-08 | vs SEA | 31 | W 10-1 | 14-17 | 4 | 29,930 | Rick Helling | Brett Tomko | Rick Helling | Brett Tomko | | 187 | 178 | 9 |
| 2000-05-09 | vs SEA | 32 | L 3-13 | 14-18 | 4 | 28,850 | Esteban Loaiza | Paul Abbott | Paul Abbott | Esteban Loaiza | | 190 | 191 | -1 |
| 2000-05-10 | vs SEA | 33 | W 7-6 | 15-18 | 4 | 27,337 | Darren Oliver | Aaron Sele | John Wetteland | Kazuhiro Sasaki | | 197 | 197 | 0 |
| 2000-05-11 | @ ANA | 34 | L 2-3 | 15-19 | 4 | 15,644 | Kenny Rogers | Kent Mercker | Shigetoshi Hasegawa | Kenny Rogers | Troy Percival | 199 | 200 | -1 |
| 2000-05-12 | @ ANA | 35 | W 13-11 | 16-19 | 4 | 35,305 | Doug Davis | Scott Schoeneweis | Doug Davis | Scott Schoeneweis | John Wetteland | 212 | 211 | 1 |
| 2000-05-13 | @ ANA | 36 | W 6-5 | 17-19 | 4 | 33,236 | Rick Helling | Jarrod Washburn | Rick Helling | Jarrod Washburn | John Wetteland | 218 | 216 | 2 |
| 2000-05-14 | @ ANA | 37 | L 6-7 | 17-20 | 4 | 27,012 | Esteban Loaiza | Jason Dickson | Shigetoshi Hasegawa | Francisco Cordero | | 224 | 223 | 1 |
| 2000-05-15 | vs TBA | 38 | W 6-5 | 18-20 | 4 | 26,683 | Darren Oliver | Dave Eiland | Darren Oliver | Rick White | John Wetteland | 230 | 228 | 2 |
| 2000-05-16 | vs TBA | 39 | W 9-7 | 19-20 | 3 | 31,033 | Mark Clark | Steve Trachsel | Jeff Zimmerman | Albie Lopez | John Wetteland | 239 | 235 | 4 |
| 2000-05-17 | vs TBA | 40 | W 11-6 | 20-20 | 3 | 27,342 | Doug Davis | Bryan Rekar | Tim Crabtree | Bryan Rekar | | 250 | 241 | 9 |
| 2000-05-18 | vs BAL | 41 | W 8-7 | 21-20 | 2 | 32,961 | Rick Helling | Sidney Ponson | Rick Helling | B.J. Ryan | John Wetteland | 258 | 248 | 10 |
| 2000-05-20 | vs BAL | 42 | W 2-1 | 22-20 | 2 | 48,164 | Esteban Loaiza | Mike Mussina | Esteban Loaiza | Mike Mussina | John Wetteland | 260 | 249 | 11 |
| 2000-05-21 | vs BAL | 43 | W 6-5 | 23-20 | 2 | 36,378 | Darren Oliver | Scott Erickson | Mike Venafro | Buddy Groom | John Wetteland | 266 | 254 | 12 |
| 2000-05-23 | @ KCA | 44 | W 4-3 | 24-20 | 2 | 19,680 | Rick Helling | Miguel Batista | Rick Helling | Miguel Batista | John Wetteland | 270 | 257 | 13 |
| 2000-05-24 | @ KCA | 45 | L 0-3 | 24-21 | 2 | 14,191 | Kenny Rogers | Jeff Suppan | Jeff Suppan | Kenny Rogers | Jerry Spradlin | 270 | 260 | 10 |
| 2000-05-25 | @ KCA | 46 | W 5-3 | 25-21 | 1 | 20,992 | Esteban Loaiza | Mac Suzuki | Esteban Loaiza | Jose Santiago | John Wetteland | 275 | 263 | 12 |
| 2000-05-26 | @ MIN | 47 | L 2-10 | 25-22 | 2 | 10,069 | Darren Oliver | Eric Milton | Eric Milton | Darren Oliver | | 277 | 273 | 4 |
| 2000-05-27 | @ MIN | 48 | L 5-10 | 25-23 | 2 | 13,923 | Mark Clark | Joe Mays | Joe Mays | Mark Clark | | 282 | 283 | -1 |
| 2000-05-28 | @ MIN | 49 | L 3-4 | 25-24 | 3 | 10,033 | Rick Helling | Sean Bergman | Sean Bergman | Rick Helling | LaTroy Hawkins | 285 | 287 | -2 |
| 2000-05-29 | @ DET | 50 | W 3-2 | 26-24 | 3 | 31,915 | Kenny Rogers | Jeff Weaver | Kenny Rogers | Jeff Weaver | John Wetteland | 288 | 289 | -1 |
| 2000-05-30 | @ DET | 51 | L 4-7 | 26-25 | 3 | 21,053 | Esteban Loaiza | Brian Moehler | Brian Moehler | Esteban Loaiza | Todd Jones | 292 | 296 | -4 |
| 2000-05-31 | @ DET | 52 | W 13-5 | 27-25 | 2 | 22,425 | Darren Oliver | Dave Mlicki | Darren Oliver | Dave Mlicki | | 305 | 301 | 4 |
| 2000-06-02 | vs ARI | 53 | L 4-5 | 27-26 | 4 | 40,770 | Rick Helling | Brian Anderson | Brian Anderson | Rick Helling | Matt Mantei | 309 | 306 | 3 |
| 2000-06-03 | vs ARI | 54 | W 4-3 | 28-26 | 3 | 46,222 | Kenny Rogers | Nelson Figueroa | Kenny Rogers | Nelson Figueroa | John Wetteland | 313 | 309 | 4 |
| 2000-06-04 | vs ARI | 55 | W 7-6 | 29-26 | 2 | 46,366 | Esteban Loaiza | Omar Daal | Matt Perisho | Byung-Hyun Kim | John Wetteland | 320 | 315 | 5 |
| 2000-06-05 | vs LAN | 56 | W 2-0 | 30-26 | 2 | 34,709 | Ryan Glynn | Kevin Brown | Ryan Glynn | Kevin Brown | John Wetteland | 322 | 315 | 7 |
| 2000-06-06 | vs LAN | 57 | L 1-7 | 30-27 | 3 | 35,847 | Mark Clark | Eric Gagne | Eric Gagne | Mark Clark | | 323 | 322 | 1 |
| 2000-06-07 | vs LAN | 58 | L 6-11 | 30-28 | 4 | 35,860 | Rick Helling | Darren Dreifort | Darren Dreifort | Rick Helling | | 329 | 333 | -4 |
| 2000-06-09 | @ COL | 59 | L 2-3 | 30-29 | 4 | 44,764 | Kenny Rogers | Pedro Astacio | Julian Tavarez | John Wetteland | | 331 | 336 | -5 |
| 2000-06-10 | @ COL | 60 | L 6-12 | 30-30 | 4 | 46,155 | Esteban Loaiza | Kevin Jarvis | Scott Karl | Esteban Loaiza | | 337 | 348 | -11 |
| 2000-06-11 | @ COL | 61 | L 8-9 | 30-31 | 4 | 42,802 | Darren Oliver | Brian Bohanon | Mike DeJean | Tim Crabtree | Jose Jimenez | 345 | 357 | -12 |
| 2000-06-13 | @ BAL | 62 | L 2-3 | 30-32 | 4 | 40,175 | Rick Helling | Scott Erickson | Scott Erickson | Rick Helling | Mike Timlin | 347 | 360 | -13 |
| 2000-06-14 | @ BAL | 63 | L 10-11 | 30-33 | 4 | 39,231 | Kenny Rogers | Pat Rapp | Mike Timlin | Tim Crabtree | | 357 | 371 | -14 |
| 2000-06-15 | @ BAL | 64 | L 1-10 | 30-34 | 4 | 46,884 | Esteban Loaiza | Sidney Ponson | Chuck McElroy | Esteban Loaiza | | 358 | 381 | -23 |
| 2000-06-16 | @ TBA | 65 | L 2-9 | 30-35 | 4 | 16,834 | Darren Oliver | Esteban Yan | Esteban Yan | Darren Oliver | | 360 | 390 | -30 |
| 2000-06-17 | @ TBA | 66 | W 5-0 | 31-35 | 4 | 22,813 | Matt Perisho | Cory Lidle | Matt Perisho | Cory Lidle | | 365 | 390 | -25 |
| 2000-06-18 | @ TBA | 67 | L 1-6 | 31-36 | 4 | 20,197 | Rick Helling | Bryan Rekar | Rick White | Rick Helling | | 366 | 396 | -30 |
| 2000-06-20 | vs MIN | 68 | W 5-2 | 32-36 | 4 | 34,608 | Kenny Rogers | Mark Redman | Kenny Rogers | Mark Redman | John Wetteland | 371 | 398 | -27 |
| 2000-06-21 | vs MIN | 69 | W 7-5 | 33-36 | 4 | 28,135 | Esteban Loaiza | Brad Radke | Esteban Loaiza | Brad Radke | John Wetteland | 378 | 403 | -25 |
| 2000-06-22 | vs MIN | 70 | L 2-3 | 33-37 | 4 | 31,320 | Matt Perisho | Joe Mays | LaTroy Hawkins | Tim Crabtree | Bob Wells | 380 | 406 | -26 |
| 2000-06-23 | vs TBA | 71 | L 4-7 | 33-38 | 4 | 42,336 | Rick Helling | Cory Lidle | Cory Lidle | Rick Helling | Roberto Hernandez | 384 | 413 | -29 |
| 2000-06-24 | vs TBA | 72 | L 7-9 | 33-39 | 4 | 48,256 | Ryan Glynn | Bryan Rekar | Rick White | Tim Crabtree | Roberto Hernandez | 391 | 422 | -31 |
| 2000-06-25 | vs TBA | 73 | W 9-5 | 34-39 | 4 | 37,107 | Kenny Rogers | Albie Lopez | Kenny Rogers | Albie Lopez | Esteban Loaiza | 400 | 427 | -27 |
| 2000-06-27 | @ OAK | 74 | L 6-7 | 34-40 | 4 | 16,081 | Matt Perisho | Tim Hudson | Tim Hudson | Matt Perisho | Jason Isringhausen | 406 | 434 | -28 |
| 2000-06-28 | @ OAK | 75 | W 5-3 | 35-40 | 4 | 25,643 | Rick Helling | Kevin Appier | Rick Helling | Kevin Appier | John Wetteland | 411 | 437 | -26 |
| 2000-06-29 | @ OAK | 76 | W 3-1 | 36-40 | 4 | 15,839 | Esteban Loaiza | Gil Heredia | Esteban Loaiza | Gil Heredia | John Wetteland | 414 | 438 | -24 |
| 2000-06-30 | vs SEA | 77 | W 13-3 | 37-40 | 4 | 31,674 | Kenny Rogers | John Halama | Kenny Rogers | John Halama | | 427 | 441 | -14 |
| 2000-07-01 | vs SEA | 78 | L 3-6 | 37-41 | 4 | 33,676 | Ryan Glynn | Paul Abbott | Paul Abbott | Mark Clark | Kazuhiro Sasaki | 430 | 447 | -17 |
| 2000-07-02 | vs SEA | 79 | L 4-11 | 37-42 | 4 | 40,478 | Matt Perisho | Aaron Sele | Aaron Sele | Matt Perisho | | 434 | 458 | -24 |
| 2000-07-03 | vs OAK | 80 | W 8-3 | 38-42 | 4 | 31,884 | Rick Helling | Kevin Appier | Rick Helling | Kevin Appier | | 442 | 461 | -19 |
| 2000-07-04 | vs OAK | 81 | W 10-7 | 39-42 | 4 | 49,187 | Esteban Loaiza | Gil Heredia | Doug Davis | Scott Service | John Wetteland | 452 | 468 | -16 |
| 2000-07-05 | vs OAK | 82 | W 9-4 | 40-42 | 4 | 28,964 | Kenny Rogers | Mark Mulder | Kenny Rogers | Mark Mulder | | 461 | 472 | -11 |
| 2000-07-07 | vs SDN | 83 | W 5-4 | 41-42 | 4 | 35,067 | Matt Perisho | Woody Williams | Doug Davis | Matt Whiteside | | 466 | 476 | -10 |
| 2000-07-08 | vs SDN | 84 | W 8-1 | 42-42 | 4 | 39,143 | Rick Helling | Adam Eaton | Rick Helling | Adam Eaton | | 474 | 477 | -3 |
| 2000-07-09 | vs SDN | 85 | L 3-4 | 42-43 | 4 | 30,070 | Kenny Rogers | Matt Clement | Matt Clement | Kenny Rogers | Trevor Hoffman | 477 | 481 | -4 |
| 2000-07-13 | @ ARI | 86 | W 6-4 | 43-43 | 4 | 32,541 | Rick Helling | Brian Anderson | Jeff Zimmerman | Byung-Hyun Kim | John Wetteland | 483 | 485 | -2 |
| 2000-07-14 | @ ARI | 87 | L 1-6 | 43-44 | 4 | 34,415 | Kenny Rogers | Armando Reynoso | Armando Reynoso | Kenny Rogers | | 484 | 491 | -7 |
| 2000-07-15 | @ ARI | 88 | W 6-5 | 44-44 | 4 | 37,856 | Matt Perisho | Randy Johnson | Jeff Zimmerman | Greg Swindell | John Wetteland | 490 | 496 | -6 |
| 2000-07-16 | @ SFN | 89 | L 4-6 | 44-45 | 4 | 40,930 | Esteban Loaiza | Shawn Estes | Shawn Estes | Esteban Loaiza | Robb Nen | 494 | 502 | -8 |
| 2000-07-17 | @ SFN | 90 | L 8-10 | 44-46 | 4 | 40,930 | Ryan Glynn | Livan Hernandez | Livan Hernandez | Doug Davis | Robb Nen | 502 | 512 | -10 |
| 2000-07-18 | @ SFN | 91 | L 3-5 | 44-47 | 4 | 40,930 | Rick Helling | Russ Ortiz | Aaron Fultz | John Wetteland | | 505 | 517 | -12 |
| 2000-07-19 | @ ANA | 92 | W 3-2 | 45-47 | 4 | 20,083 | Kenny Rogers | Kent Bottenfield | Kenny Rogers | Kent Bottenfield | John Wetteland | 508 | 519 | -11 |
| 2000-07-20 | @ ANA | 93 | L 1-6 | 45-48 | 4 | 23,150 | Darren Oliver | Seth Etherton | Seth Etherton | Darren Oliver | Shigetoshi Hasegawa | 509 | 525 | -16 |
| 2000-07-21 | @ SEA | 94 | L 3-12 | 45-49 | 4 | 44,765 | Matt Perisho | Paul Abbott | Paul Abbott | Matt Perisho | | 512 | 537 | -25 |
| 2000-07-22 | @ SEA | 95 | L 5-13 | 45-50 | 4 | 44,381 | Ryan Glynn | John Halama | John Halama | Ryan Glynn | | 517 | 550 | -33 |
| 2000-07-23 | @ SEA | 96 | W 3-2 | 46-50 | 4 | 45,319 | Rick Helling | Freddy Garcia | Rick Helling | Arthur Rhodes | John Wetteland | 520 | 552 | -32 |
| 2000-07-24 | vs ANA | 97 | L 5-6 | 46-51 | 4 | 33,201 | Kenny Rogers | Kent Bottenfield | Shigetoshi Hasegawa | Tim Crabtree | Troy Percival | 525 | 558 | -33 |
| 2000-07-25 | vs ANA | 98 | W 9-6 | 47-51 | 4 | 34,272 | Darren Oliver | Seth Etherton | Doug Davis | Mike Holtz | John Wetteland | 534 | 564 | -30 |
| 2000-07-26 | vs ANA | 99 | W 6-5 | 48-51 | 4 | 27,858 | Matt Perisho | Scott Schoeneweis | John Wetteland | Al Levine | | 540 | 569 | -29 |
| 2000-07-27 | vs DET | 100 | W 7-3 | 49-51 | 4 | 37,748 | Ryan Glynn | Steve Sparks | Ryan Glynn | Steve Sparks | Jeff Zimmerman | 547 | 572 | -25 |
| 2000-07-28 | vs DET | 101 | W 11-5 | 50-51 | 4 | 47,783 | Rick Helling | Brian Moehler | Rick Helling | Brian Moehler | | 558 | 577 | -19 |
| 2000-07-29 | vs DET | 102 | L 2-10 | 50-52 | 4 | 48,150 | Kenny Rogers | Hideo Nomo | Hideo Nomo | Kenny Rogers | | 560 | 587 | -27 |
| 2000-07-30 | vs DET | 103 | L 7-8 | 50-53 | 4 | 40,167 | Darren Oliver | Willie Blair | Willie Blair | Darren Oliver | Todd Jones | 567 | 595 | -28 |
| 2000-08-01 | vs CHA | 104 | L 3-4 | 50-54 | 4 | 37,784 | Ryan Glynn | James Baldwin | Bob Howry | John Wetteland | | 570 | 599 | -29 |
| 2000-08-02 | vs CHA | 105 | W 7-2 | 51-54 | 4 | 36,786 | Rick Helling | Jon Garland | Rick Helling | Jon Garland | Tim Crabtree | 577 | 601 | -24 |
| 2000-08-03 | @ TOR | 106 | L 1-3 | 51-55 | 4 | 24,825 | Kenny Rogers | Frank Castillo | Frank Castillo | Kenny Rogers | Billy Koch | 578 | 604 | -26 |
| 2000-08-04 | @ TOR | 107 | L 8-10 | 51-56 | 4 | 23,518 | Matt Perisho | Steve Trachsel | Paul Quantrill | Mike Venafro | Billy Koch | 586 | 614 | -28 |
| 2000-08-05 | @ TOR | 108 | L 5-8 | 51-57 | 4 | 26,143 | Doug Davis | David Wells | David Wells | Doug Davis | Billy Koch | 591 | 622 | -31 |
| 2000-08-06 | @ TOR | 109 | W 11-6 | 52-57 | 4 | 28,780 | Ryan Glynn | Kelvim Escobar | Ryan Glynn | Kelvim Escobar | | 602 | 628 | -26 |
| 2000-08-07 | @ CLE | 110 | L 0-2 | 52-58 | 4 | 43,258 | Rick Helling | Steve Woodard | Steve Reed | Rick Helling | Bob Wickman | 602 | 630 | -28 |
| 2000-08-08 | @ CLE | 111 | W 11-2 | 53-58 | 4 | 43,238 | Kenny Rogers | Jason Bere | Kenny Rogers | Jason Bere | | 613 | 632 | -19 |
| 2000-08-09 | @ CLE | 112 | L 4-6 | 53-59 | 4 | 43,333 | Matt Perisho | Dave Burba | Justin Speier | Matt Perisho | Bob Wickman | 617 | 638 | -21 |
| 2000-08-11 | vs BOS | 113 | L 3-7 | 53-60 | 4 | 39,911 | Ryan Glynn | Rolando Arrojo | Rolando Arrojo | Ryan Glynn | | 620 | 645 | -25 |
| 2000-08-12 | vs BOS | 114 | W 6-3 | 54-60 | 4 | 43,822 | Rick Helling | Tim Wakefield | Rick Helling | Tim Wakefield | | 626 | 648 | -22 |
| 2000-08-13 | vs BOS | 115 | L 2-4 | 54-61 | 4 | 28,927 | Kenny Rogers | Tomo Ohka | Tomo Ohka | Kenny Rogers | Derek Lowe | 628 | 652 | -24 |
| 2000-08-14 | vs NYA | 116 | L 3-7 | 54-62 | 4 | 36,260 | Matt Perisho | Andy Pettitte | Andy Pettitte | Matt Perisho | | 631 | 659 | -28 |
| 2000-08-15 | vs NYA | 117 | L 2-10 | 54-63 | 4 | 35,365 | Doug Davis | David Cone | David Cone | Doug Davis | Dwight Gooden | 633 | 669 | -36 |
| 2000-08-16 | vs NYA | 118 | W 5-0 | 55-63 | 4 | 34,446 | Brian Sikorski | Orlando Hernandez | Brian Sikorski | Orlando Hernandez | | 638 | 669 | -31 |
| 2000-08-17 | @ BOS | 119 | L 7-8 | 55-64 | 4 | 33,510 | Rick Helling | Tim Wakefield | Rich Garces | John Wetteland | | 645 | 677 | -32 |
| 2000-08-18 | @ BOS | 120 | L 4-6 | 55-65 | 4 | 33,009 | Kenny Rogers | Tomo Ohka | Tomo Ohka | Kenny Rogers | Derek Lowe | 649 | 683 | -34 |
| 2000-08-19 | @ BOS | 121 | L 0-9 | 55-66 | 4 | 33,222 | Matt Perisho | Pedro Martinez | Pedro Martinez | Matt Perisho | | 649 | 692 | -43 |
| 2000-08-20 | @ BOS | 122 | W 6-2 | 56-66 | 4 | 32,467 | Doug Davis | Jeff Fassero | Doug Davis | Jeff Fassero | | 655 | 694 | -39 |
| 2000-08-21 | @ NYA | 123 | L 3-12 | 56-67 | 4 | 16,310 | Brian Sikorski | Orlando Hernandez | Orlando Hernandez | Brian Sikorski | | 658 | 706 | -48 |
| 2000-08-22 | @ NYA | 124 | W 5-4 | 57-67 | 4 | 39,915 | Rick Helling | Denny Neagle | Tim Crabtree | Denny Neagle | John Wetteland | 663 | 710 | -47 |
| 2000-08-23 | @ NYA | 125 | L 9-10 | 57-68 | 4 | 33,081 | Kenny Rogers | Roger Clemens | Mariano Rivera | Tim Crabtree | | 672 | 720 | -48 |
| 2000-08-24 | @ NYA | 126 | L 7-8 | 57-69 | 4 | 44,578 | Matt Perisho | Andy Pettitte | Andy Pettitte | Matt Perisho | Mariano Rivera | 679 | 728 | -49 |
| 2000-08-25 | vs TOR | 127 | W 1-0 | 58-69 | 4 | 35,365 | Doug Davis | David Wells | Mike Venafro | Billy Koch | | 680 | 728 | -48 |
| 2000-08-26 | vs TOR | 128 | L 3-9 | 58-70 | 4 | 39,388 | Brian Sikorski | Joey Hamilton | Joey Hamilton | Brian Sikorski | Pedro Borbon | 683 | 737 | -54 |
| 2000-08-27 | vs TOR | 129 | L 4-6 | 58-71 | 4 | 21,896 | Rick Helling | Steve Trachsel | Steve Trachsel | Rick Helling | Billy Koch | 687 | 743 | -56 |
| 2000-08-28 | vs CLE | 130 | L 2-5 | 58-72 | 4 | 22,134 | Kenny Rogers | Bartolo Colon | Bartolo Colon | Kenny Rogers | Bob Wickman | 689 | 748 | -59 |
| 2000-08-29 | vs CLE | 131 | L 1-12 | 58-73 | 4 | 22,389 | Ryan Glynn | Steve Woodard | Steve Woodard | Ryan Glynn | | 690 | 760 | -70 |
| 2000-08-30 | vs CLE | 132 | L 3-5 | 58-74 | 4 | 24,215 | Doug Davis | Dave Burba | Dave Burba | Doug Davis | Bob Wickman | 693 | 765 | -72 |
| 2000-08-31 | vs CLE | 133 | W 14-7 | 59-74 | 4 | 27,333 | Brian Sikorski | Jason Bere | Mike Venafro | Steve Karsay | | 707 | 772 | -65 |
| 2000-09-01 | @ DET | 134 | L 5-7 | 59-75 | 4 | 31,471 | Rick Helling | Steve Sparks | Steve Sparks | Rick Helling | Todd Jones | 712 | 779 | -67 |
| 2000-09-02 | @ DET | 135 | L 3-5 | 59-76 | 4 | 35,060 | Kenny Rogers | Willie Blair | Willie Blair | Kenny Rogers | Matt Anderson | 715 | 784 | -69 |
| 2000-09-03 | @ DET | 136 | W 4-1 | 60-76 | 4 | 30,242 | Ryan Glynn | Jeff Weaver | Ryan Glynn | Jeff Weaver | John Wetteland | 719 | 785 | -66 |
| 2000-09-04 | @ CHA | 137 | W 5-4 | 61-76 | 4 | 29,614 | Doug Davis | Jon Garland | Doug Davis | Jon Garland | John Wetteland | 724 | 789 | -65 |
| 2000-09-05 | @ CHA | 138 | W 2-1 | 62-76 | 4 | 13,899 | Darren Oliver | Mike Sirotka | Jonathan Johnson | Bob Howry | John Wetteland | 726 | 790 | -64 |
| 2000-09-06 | @ CHA | 139 | L 1-13 | 62-77 | 4 | 15,622 | Rick Helling | Kip Wells | Kip Wells | Rick Helling | | 727 | 803 | -76 |
| 2000-09-07 | @ CHA | 140 | L 6-10 | 62-78 | 4 | 18,219 | Kenny Rogers | Jim Parque | Lorenzo Barcelo | Jeff Zimmerman | Keith Foulke | 733 | 813 | -80 |
| 2000-09-08 | @ KCA | 141 | W 6-5 | 63-78 | 4 | 14,705 | Ryan Glynn | Blake Stein | Ryan Glynn | Blake Stein | John Wetteland | 739 | 818 | -79 |
| 2000-09-09 | @ KCA | 142 | W 6-5 | 64-78 | 4 | 26,009 | Doug Davis | Mac Suzuki | Jeff Zimmerman | Mac Suzuki | John Wetteland | 745 | 823 | -78 |
| 2000-09-10 | @ KCA | 143 | L 8-13 | 64-79 | 4 | 13,012 | Darren Oliver | Jeff Suppan | Jeff Suppan | Darren Oliver | | 753 | 836 | -83 |
| 2000-09-12 | vs BAL | 144 | W 9-1 | 66-79 | 4 | 0 | Rick Helling | John Parrish | Rick Helling | John Parrish | | 762 | 837 | -75 |
| 2000-09-12 | vs BAL | 145 | W 6-5 | 66-79 | 4 | 24,221 | Kenny Rogers | Jay Spurgeon | Kenny Rogers | Jay Spurgeon | John Wetteland | 768 | 842 | -74 |
| 2000-09-13 | vs BAL | 146 | L 4-9 | 66-80 | 4 | 24,819 | Ryan Glynn | Pat Rapp | Pat Rapp | Ryan Glynn | | 772 | 851 | -79 |
| 2000-09-14 | vs KCA | 147 | W 8-1 | 67-80 | 4 | 26,978 | Doug Davis | Mac Suzuki | Doug Davis | Mac Suzuki | Tim Crabtree | 780 | 852 | -72 |
| 2000-09-15 | vs KCA | 148 | W 12-11 | 68-80 | 4 | 32,050 | Darren Oliver | Jeff Suppan | John Wetteland | Jose Santiago | | 792 | 863 | -71 |
| 2000-09-16 | vs KCA | 149 | L 5-8 | 68-81 | 4 | 37,668 | Brian Sikorski | Brian Meadows | Brian Meadows | Brian Sikorski | | 797 | 871 | -74 |
| 2000-09-17 | vs KCA | 150 | W 6-5 | 69-81 | 4 | 28,473 | Kenny Rogers | Dan Reichert | Kenny Rogers | Dan Reichert | John Wetteland | 803 | 876 | -73 |
| 2000-09-18 | @ MIN | 151 | L 1-3 | 69-82 | 4 | 7,040 | Rick Helling | Joe Mays | Joe Mays | Rick Helling | Eddie Guardado | 804 | 879 | -75 |
| 2000-09-19 | @ MIN | 152 | L 7-15 | 69-83 | 4 | 6,089 | Ryan Glynn | Matt Kinney | Matt Kinney | Ryan Glynn | | 811 | 894 | -83 |
| 2000-09-20 | @ MIN | 153 | W 6-4 | 70-83 | 4 | 6,072 | Doug Davis | J.C. Romero | John Wetteland | Travis Miller | Mike Venafro | 817 | 898 | -81 |
| 2000-09-22 | vs ANA | 154 | L 1-2 | 70-84 | 4 | 38,739 | Darren Oliver | Lou Pote | Ben Weber | Darren Oliver | Troy Percival | 818 | 900 | -82 |
| 2000-09-23 | vs ANA | 155 | L 4-15 | 70-85 | 4 | 45,543 | Rick Helling | Derrick Turnbow | Scott Karl | Rick Helling | | 822 | 915 | -93 |
| 2000-09-24 | vs ANA | 156 | L 2-9 | 70-86 | 4 | 32,061 | Kenny Rogers | Ramon Ortiz | Ramon Ortiz | Jonathan Johnson | | 824 | 924 | -100 |
| 2000-09-26 | @ SEA | 157 | L 0-5 | 70-87 | 4 | 31,399 | Ryan Glynn | Aaron Sele | Aaron Sele | Ryan Glynn | | 824 | 929 | -105 |
| 2000-09-27 | @ SEA | 158 | L 4-6 | 70-88 | 4 | 35,901 | Doug Davis | Freddy Garcia | Freddy Garcia | Doug Davis | Kazuhiro Sasaki | 828 | 935 | -107 |
| 2000-09-28 | @ SEA | 159 | W 13-6 | 71-88 | 4 | 43,264 | Rick Helling | Jamie Moyer | Rick Helling | Brett Tomko | | 841 | 941 | -100 |
| 2000-09-29 | @ OAK | 160 | L 5-7 | 71-89 | 4 | 30,522 | Kenny Rogers | Omar Olivares | Jim Mecir | Francisco Cordero | Jason Isringhausen | 846 | 948 | -102 |
| 2000-09-30 | @ OAK | 161 | L 2-23 | 71-90 | 4 | 35,546 | Darren Oliver | Barry Zito | Barry Zito | Darren Oliver | | 848 | 971 | -123 |
| 2000-10-01 | @ OAK | 162 | L 0-3 | 71-91 | 4 | 45,606 | Ryan Glynn | Tim Hudson | Tim Hudson | Ryan Glynn | Jason Isringhausen | 848 | 974 | -126 |