| 1980-04-11 | @ PHI | 1 | L 3-6 | 0-1 | 6 | 48,460 | Steve Rogers | Steve Carlton | Steve Carlton | Steve Rogers | | 3 | 6 | -3 |
| 1980-04-12 | @ PHI | 2 | L 2-6 | 0-2 | 6 | 22,065 | Bill Lee | Dick Ruthven | Dick Ruthven | Bill Lee | Tug McGraw | 5 | 12 | -7 |
| 1980-04-13 | @ PHI | 3 | W 5-4 | 1-2 | 5 | 28,132 | Scott Sanderson | Larry Christenson | Elias Sosa | Lerrin LaGrow | | 10 | 16 | -6 |
| 1980-04-15 | @ NYN | 4 | W 7-3 | 2-2 | 2 | 3,207 | Steve Rogers | Craig Swan | Steve Rogers | Craig Swan | Fred Norman | 17 | 19 | -2 |
| 1980-04-16 | @ NYN | 5 | L 2-3 | 2-3 | 5 | 2,052 | Bill Lee | Ray Burris | Ray Burris | Bill Lee | Neil Allen | 19 | 22 | -3 |
| 1980-04-18 | vs PHI | 6 | W 7-5 | 3-3 | 3 | 41,222 | Scott Sanderson | Dick Ruthven | Scott Sanderson | Dick Ruthven | Woodie Fryman | 26 | 27 | -1 |
| 1980-04-19 | vs PHI | 7 | L 4-13 | 3-4 | 5 | 23,088 | Steve Rogers | Larry Christenson | Larry Christenson | Steve Rogers | Dickie Noles | 30 | 40 | -10 |
| 1980-04-20 | vs PHI | 8 | W 7-6 | 4-4 | 3 | 25,722 | Bill Lee | Randy Lerch | Elias Sosa | Tug McGraw | | 37 | 46 | -9 |
| 1980-04-21 | vs PIT | 9 | L 1-7 | 4-5 | 3 | 10,327 | Ross Grimsley | John Candelaria | John Candelaria | Ross Grimsley | | 38 | 53 | -15 |
| 1980-04-22 | vs PIT | 10 | L 3-5 | 4-6 | 4 | 7,373 | Scott Sanderson | Jim Bibby | Jim Bibby | Scott Sanderson | Kent Tekulve | 41 | 58 | -17 |
| 1980-04-23 | vs PIT | 11 | W 3-2 | 5-6 | 3 | 8,161 | Steve Rogers | Bert Blyleven | Steve Rogers | Bert Blyleven | | 44 | 60 | -16 |
| 1980-04-25 | @ ATL | 12 | L 7-8 | 5-7 | 4 | 6,929 | Bill Lee | Tommy Boggs | Larry Bradford | Stan Bahnsen | | 51 | 68 | -17 |
| 1980-04-26 | @ ATL | 13 | W 4-3 | 6-7 | 3 | 13,705 | Ross Grimsley | Phil Niekro | Ross Grimsley | Phil Niekro | Woodie Fryman | 55 | 71 | -16 |
| 1980-04-27 | @ ATL | 14 | L 3-6 | 6-8 | 4 | 12,917 | Scott Sanderson | Larry McWilliams | Larry McWilliams | Scott Sanderson | Al Hrabosky | 58 | 77 | -19 |
| 1980-04-29 | @ PIT | 15 | L 4-5 | 6-9 | 5 | 8,498 | Steve Rogers | Bert Blyleven | Eddie Solomon | Elias Sosa | | 62 | 82 | -20 |
| 1980-04-30 | @ PIT | 16 | L 0-5 | 6-10 | 5 | 8,545 | Bill Lee | Jim Bibby | Jim Bibby | Bill Lee | | 62 | 87 | -25 |
| 1980-05-01 | @ PIT | 17 | L 1-2 | 6-11 | 5 | 8,426 | David Palmer | John Candelaria | Kent Tekulve | Woodie Fryman | | 63 | 89 | -26 |
| 1980-05-02 | vs SFN | 18 | W 4-3 | 7-11 | 5 | 8,953 | Ross Grimsley | Bob Knepper | Stan Bahnsen | Gary Lavelle | | 67 | 92 | -25 |
| 1980-05-03 | vs SFN | 19 | L 2-3 | 7-12 | 5 | 18,622 | Scott Sanderson | Ed Whitson | Randy Moffitt | Elias Sosa | Al Holland | 69 | 95 | -26 |
| 1980-05-04 | vs SFN | 20 | L 4-8 | 8-13 | 5 | 0 | Steve Rogers | John Montefusco | John Montefusco | Steve Rogers | Greg Minton | 73 | 103 | -30 |
| 1980-05-04 | vs SFN | 21 | W 6-4 | 8-13 | 5 | 33,483 | Bill Lee | Ed Halicki | Stan Bahnsen | Randy Moffitt | Elias Sosa | 79 | 107 | -28 |
| 1980-05-05 | vs HOU | 22 | W 10-1 | 9-13 | 5 | 5,477 | David Palmer | J.R. Richard | David Palmer | J.R. Richard | | 89 | 108 | -19 |
| 1980-05-06 | vs HOU | 23 | L 4-8 | 9-14 | 5 | 5,503 | Ross Grimsley | Joe Niekro | Joe Niekro | Ross Grimsley | | 93 | 116 | -23 |
| 1980-05-07 | vs HOU | 24 | W 3-0 | 10-14 | 5 | 7,386 | Scott Sanderson | Nolan Ryan | Scott Sanderson | Nolan Ryan | Woodie Fryman | 96 | 116 | -20 |
| 1980-05-09 | vs NYN | 25 | L 1-2 | 10-15 | 5 | 8,674 | Steve Rogers | Craig Swan | Craig Swan | Steve Rogers | | 97 | 118 | -21 |
| 1980-05-10 | vs NYN | 26 | W 5-3 | 11-15 | 5 | 14,012 | Bill Lee | Mark Bomback | Bill Lee | Kevin Kobel | Elias Sosa | 102 | 121 | -19 |
| 1980-05-13 | @ HOU | 27 | W 3-2 | 12-15 | 5 | 24,835 | David Palmer | Nolan Ryan | David Palmer | Nolan Ryan | Woodie Fryman | 105 | 123 | -18 |
| 1980-05-14 | @ HOU | 28 | W 1-0 | 13-15 | 5 | 20,636 | Scott Sanderson | Ken Forsch | Scott Sanderson | Ken Forsch | Woodie Fryman | 106 | 123 | -17 |
| 1980-05-16 | vs CIN | 29 | W 2-1 | 14-15 | 4 | 14,457 | Steve Rogers | Tom Seaver | Steve Rogers | Tom Seaver | Woodie Fryman | 108 | 124 | -16 |
| 1980-05-17 | vs CIN | 30 | W 9-6 | 15-15 | 4 | 22,702 | Bill Lee | Mike LaCoss | Stan Bahnsen | Tom Hume | Elias Sosa | 117 | 130 | -13 |
| 1980-05-19 | vs ATL | 31 | W 11-8 | 16-15 | 3 | 20,656 | David Palmer | Larry McWilliams | David Palmer | Larry McWilliams | Woodie Fryman | 128 | 138 | -10 |
| 1980-05-20 | vs ATL | 32 | L 0-1 | 16-16 | 3 | 11,071 | Scott Sanderson | Phil Niekro | Phil Niekro | Scott Sanderson | | 128 | 139 | -11 |
| 1980-05-21 | vs ATL | 33 | W 3-2 | 17-16 | 3 | 13,606 | Steve Rogers | Preston Hanna | Steve Rogers | Gene Garber | | 131 | 141 | -10 |
| 1980-05-23 | @ CIN | 34 | W 7-4 | 18-16 | 3 | 23,311 | Bill Lee | Mike LaCoss | Bill Lee | Mike LaCoss | | 138 | 145 | -7 |
| 1980-05-24 | @ CIN | 35 | L 0-2 | 18-17 | 3 | 30,024 | David Palmer | Frank Pastore | Frank Pastore | David Palmer | | 138 | 147 | -9 |
| 1980-05-25 | @ CIN | 36 | W 7-4 | 19-17 | 3 | 27,433 | Scott Sanderson | Charlie Leibrandt | Scott Sanderson | Charlie Leibrandt | Stan Bahnsen | 145 | 151 | -6 |
| 1980-05-26 | @ CHN | 37 | W 4-0 | 20-17 | 3 | 31,845 | Steve Rogers | Guillermo Hernandez | Steve Rogers | Guillermo Hernandez | | 149 | 151 | -2 |
| 1980-05-27 | @ CHN | 38 | L 2-4 | 20-18 | 3 | 11,677 | Bill Lee | Dennis Lamp | Dennis Lamp | Bill Lee | Dick Tidrow | 151 | 155 | -4 |
| 1980-05-28 | @ CHN | 39 | L 4-8 | 20-19 | 3 | 12,778 | David Palmer | Mike Krukow | Dennis Lamp | Dale Murray | | 155 | 163 | -8 |
| 1980-05-30 | @ SLN | 40 | W 10-4 | 21-19 | 3 | 13,229 | Scott Sanderson | Jim Kaat | Scott Sanderson | Jim Kaat | | 165 | 167 | -2 |
| 1980-05-31 | @ SLN | 41 | L 6-8 | 21-20 | 3 | 19,106 | Steve Rogers | Bob Forsch | Bob Forsch | Steve Rogers | Pete Vuckovich | 171 | 175 | -4 |
| 1980-06-01 | @ SLN | 42 | W 7-6 | 22-20 | 3 | 30,016 | Bill Lee | Silvio Martinez | Stan Bahnsen | George Frazier | Fred Norman | 178 | 181 | -3 |
| 1980-06-02 | vs CHN | 43 | W 8-7 | 23-20 | 2 | 15,271 | David Palmer | Mike Krukow | Woodie Fryman | Lynn McGlothen | | 186 | 188 | -2 |
| 1980-06-03 | vs CHN | 44 | L 2-5 | 23-21 | 2 | 22,502 | Ross Grimsley | Rick Reuschel | Rick Reuschel | Ross Grimsley | | 188 | 193 | -5 |
| 1980-06-04 | vs CHN | 45 | W 8-1 | 24-21 | 2 | 13,297 | Steve Rogers | Lynn McGlothen | Steve Rogers | Lynn McGlothen | | 196 | 194 | 2 |
| 1980-06-05 | vs CHN | 46 | W 2-0 | 25-21 | 2 | 19,420 | Scott Sanderson | Dennis Lamp | Scott Sanderson | Dennis Lamp | | 198 | 194 | 4 |
| 1980-06-06 | vs SLN | 47 | W 7-2 | 26-21 | 2 | 25,151 | Bill Lee | Bob Forsch | Bill Lee | Bob Forsch | | 205 | 196 | 9 |
| 1980-06-07 | vs SLN | 48 | W 2-1 | 27-21 | 2 | 32,068 | David Palmer | Pete Vuckovich | Elias Sosa | Jim Otten | | 207 | 197 | 10 |
| 1980-06-08 | vs SLN | 49 | W 6-4 | 29-21 | 1 | 0 | Steve Rogers | John Fulgham | Steve Rogers | John Fulgham | Woodie Fryman | 213 | 201 | 12 |
| 1980-06-08 | vs SLN | 50 | W 9-4 | 29-21 | 1 | 46,871 | Ross Grimsley | Roy Thomas | Ross Grimsley | Roy Thomas | | 222 | 205 | 17 |
| 1980-06-10 | vs SDN | 51 | W 8-4 | 30-21 | 1 | 17,439 | Scott Sanderson | Rick Wise | Stan Bahnsen | Eric Rasmussen | Elias Sosa | 230 | 209 | 21 |
| 1980-06-11 | vs SDN | 52 | W 7-6 | 31-21 | 1 | 13,948 | Bill Gullickson | John Curtis | Elias Sosa | Bob Shirley | | 237 | 215 | 22 |
| 1980-06-12 | vs SDN | 53 | W 9-1 | 32-21 | 1 | 20,724 | Charlie Lea | Gary Lucas | Charlie Lea | Gary Lucas | | 246 | 216 | 30 |
| 1980-06-13 | vs LAN | 54 | W 4-3 | 33-21 | 1 | 34,655 | Steve Rogers | Don Sutton | Steve Rogers | Steve Howe | | 250 | 219 | 31 |
| 1980-06-14 | vs LAN | 55 | L 0-8 | 33-22 | 1 | 44,585 | Ross Grimsley | Burt Hooton | Burt Hooton | Ross Grimsley | | 250 | 227 | 23 |
| 1980-06-15 | vs LAN | 56 | L 0-1 | 33-23 | 1 | 36,176 | Bill Gullickson | Bob Welch | Bob Welch | Bill Gullickson | | 250 | 228 | 22 |
| 1980-06-16 | @ SFN | 57 | L 1-5 | 33-24 | 2 | 4,756 | Charlie Lea | Ed Whitson | Ed Whitson | Charlie Lea | | 251 | 233 | 18 |
| 1980-06-17 | @ SFN | 58 | W 2-1 | 34-24 | 1 | 19,362 | David Palmer | Vida Blue | David Palmer | Vida Blue | Woodie Fryman | 253 | 234 | 19 |
| 1980-06-18 | @ LAN | 59 | L 7-8 | 34-25 | 2 | 41,229 | Steve Rogers | Don Sutton | Charlie Hough | Elias Sosa | Steve Howe | 260 | 242 | 18 |
| 1980-06-19 | @ LAN | 60 | L 3-5 | 34-26 | 2 | 35,819 | Bill Gullickson | Burt Hooton | Bobby Castillo | Woodie Fryman | | 263 | 247 | 16 |
| 1980-06-20 | @ SDN | 61 | L 2-4 | 34-27 | 2 | 14,266 | Scott Sanderson | Steve Mura | Steve Mura | Scott Sanderson | Bob Shirley | 265 | 251 | 14 |
| 1980-06-21 | @ SDN | 62 | W 7-4 | 35-27 | 1 | 13,726 | Charlie Lea | John Curtis | Charlie Lea | John Curtis | Elias Sosa | 272 | 255 | 17 |
| 1980-06-22 | @ SDN | 63 | W 2-0 | 36-27 | 1 | 14,388 | Steve Rogers | Gary Lucas | Steve Rogers | Gary Lucas | | 274 | 255 | 19 |
| 1980-06-24 | @ PHI | 64 | W 7-6 | 37-27 | 1 | 32,101 | David Palmer | Dickie Noles | Elias Sosa | Tug McGraw | | 281 | 261 | 20 |
| 1980-06-25 | @ PHI | 65 | L 1-2 | 37-28 | 1 | 31,416 | Bill Gullickson | Bob Walk | Ron Reed | Stan Bahnsen | | 282 | 263 | 19 |
| 1980-06-26 | @ PHI | 66 | W 1-0 | 38-28 | 1 | 31,696 | Scott Sanderson | Randy Lerch | Scott Sanderson | Randy Lerch | | 283 | 263 | 20 |
| 1980-06-27 | vs PIT | 67 | L 4-6 | 38-29 | 1 | 44,232 | Steve Rogers | Bert Blyleven | Enrique Romo | Steve Rogers | Don Robinson | 287 | 269 | 18 |
| 1980-06-28 | vs PIT | 68 | L 3-4 | 38-30 | 1 | 38,065 | Charlie Lea | Jim Bibby | Jim Bibby | Charlie Lea | Enrique Romo | 290 | 273 | 17 |
| 1980-06-29 | vs PIT | 69 | W 4-1 | 39-30 | 1 | 46,186 | David Palmer | Eddie Solomon | David Palmer | Eddie Solomon | Fred Norman | 294 | 274 | 20 |
| 1980-06-30 | vs PHI | 70 | L 5-7 | 39-31 | 1 | 36,347 | Bill Gullickson | Dickie Noles | Dickie Noles | Bill Gullickson | Ron Reed | 299 | 281 | 18 |
| 1980-07-01 | vs PHI | 71 | L 4-5 | 39-32 | 1 | 33,761 | Scott Sanderson | Randy Lerch | Randy Lerch | Woodie Fryman | Lerrin LaGrow | 303 | 286 | 17 |
| 1980-07-02 | vs PHI | 72 | W 6-1 | 40-32 | 1 | 23,233 | Steve Rogers | Steve Carlton | Steve Rogers | Steve Carlton | | 309 | 287 | 22 |
| 1980-07-03 | @ NYN | 73 | L 2-7 | 40-33 | 1 | 12,585 | Charlie Lea | Ray Burris | Tom Hausman | Charlie Lea | | 311 | 294 | 17 |
| 1980-07-04 | @ NYN | 74 | L 5-9 | 41-34 | 1 | 0 | David Palmer | Pat Zachry | Ed Glynn | David Palmer | Jeff Reardon | 316 | 303 | 13 |
| 1980-07-04 | @ NYN | 75 | W 6-5 | 41-34 | 1 | 25,323 | Bill Gullickson | Mark Bomback | Woodie Fryman | Mark Bomback | Elias Sosa | 322 | 308 | 14 |
| 1980-07-05 | @ NYN | 76 | L 5-7 | 41-35 | 1 | 51,097 | Scott Sanderson | Pete Falcone | Pete Falcone | Scott Sanderson | Neil Allen | 327 | 315 | 12 |
| 1980-07-06 | @ NYN | 77 | W 9-4 | 42-35 | 1 | 21,880 | Steve Rogers | Craig Swan | Woodie Fryman | Jeff Reardon | | 336 | 319 | 17 |
| 1980-07-10 | vs SLN | 78 | W 4-3 | 43-35 | 1 | 31,019 | David Palmer | Bob Forsch | David Palmer | John Littlefield | Woodie Fryman | 340 | 322 | 18 |
| 1980-07-11 | vs SLN | 79 | L 3-5 | 43-36 | 2 | 25,910 | Steve Rogers | Pete Vuckovich | Silvio Martinez | Woodie Fryman | John Littlefield | 343 | 327 | 16 |
| 1980-07-12 | vs CHN | 80 | W 10-2 | 44-37 | 2 | 0 | Scott Sanderson | Rick Reuschel | Scott Sanderson | Rick Reuschel | | 353 | 329 | 24 |
| 1980-07-12 | vs CHN | 81 | L 6-8 | 44-37 | 2 | 48,620 | Bill Lee | Dennis Lamp | Dick Tidrow | Stan Bahnsen | Bruce Sutter | 359 | 337 | 22 |
| 1980-07-13 | vs CHN | 82 | W 2-1 | 45-37 | 2 | 31,095 | Charlie Lea | Doug Capilla | Stan Bahnsen | Doug Capilla | | 361 | 338 | 23 |
| 1980-07-15 | @ CIN | 83 | L 7-11 | 45-38 | 1 | 21,589 | David Palmer | Paul Moskau | Paul Moskau | David Palmer | | 368 | 349 | 19 |
| 1980-07-16 | @ CIN | 84 | W 6-4 | 46-38 | 1 | 20,023 | Steve Rogers | Mario Soto | Steve Rogers | Mario Soto | Stan Bahnsen | 374 | 353 | 21 |
| 1980-07-17 | @ CIN | 85 | W 6-1 | 47-38 | 1 | 20,290 | Scott Sanderson | Mike LaCoss | Scott Sanderson | Mike LaCoss | | 380 | 354 | 26 |
| 1980-07-18 | @ HOU | 86 | W 5-4 | 48-38 | 1 | 26,389 | Bill Lee | Vern Ruhle | Woodie Fryman | Dave Smith | Fred Norman | 385 | 358 | 27 |
| 1980-07-19 | @ HOU | 87 | L 2-4 | 49-39 | 2 | 40,499 | Charlie Lea | Joaquin Andujar | Joaquin Andujar | Charlie Lea | Dave Smith | 387 | 362 | 25 |
| 1980-07-19 | @ HOU | 88 | W 5-2 | 49-39 | 2 | 39,507 | Bill Gullickson | Gordie Pladson | Bill Gullickson | Gordie Pladson | | 392 | 364 | 28 |
| 1980-07-20 | @ HOU | 89 | L 3-4 | 49-40 | 2 | 28,513 | Steve Rogers | Nolan Ryan | Joe Sambito | Fred Norman | | 395 | 368 | 27 |
| 1980-07-21 | @ ATL | 90 | W 8-6 | 50-40 | 2 | 6,894 | Scott Sanderson | Rick Matula | Scott Sanderson | Rick Matula | Elias Sosa | 403 | 374 | 29 |
| 1980-07-22 | @ ATL | 91 | L 5-7 | 50-41 | 2 | 37,108 | Bill Lee | Phil Niekro | Phil Niekro | Stan Bahnsen | Rick Camp | 408 | 381 | 27 |
| 1980-07-23 | @ ATL | 92 | L 5-6 | 50-42 | 2 | 10,873 | Charlie Lea | Doyle Alexander | Rick Camp | Bill Gullickson | | 413 | 387 | 26 |
| 1980-07-25 | vs HOU | 93 | L 8-9 | 50-43 | 2 | 50,217 | Steve Rogers | Nolan Ryan | Frank LaCorte | Elias Sosa | | 421 | 396 | 25 |
| 1980-07-26 | vs HOU | 94 | W 2-1 | 51-43 | 2 | 42,400 | Scott Sanderson | Ken Forsch | Stan Bahnsen | Frank LaCorte | | 423 | 397 | 26 |
| 1980-07-27 | vs HOU | 95 | L 3-6 | 51-44 | 2 | 41,107 | Bill Lee | Joe Niekro | Joe Niekro | Bill Lee | Dave Smith | 426 | 403 | 23 |
| 1980-07-28 | vs CIN | 96 | L 2-3 | 52-45 | 2 | 0 | Charlie Lea | Mike LaCoss | Doug Bair | Charlie Lea | Tom Hume | 428 | 406 | 22 |
| 1980-07-28 | vs CIN | 97 | W 5-4 | 52-45 | 2 | 40,301 | Fred Norman | Mario Soto | Fred Norman | Mario Soto | Woodie Fryman | 433 | 410 | 23 |
| 1980-07-29 | vs CIN | 98 | W 4-1 | 53-45 | 2 | 28,445 | Bill Gullickson | Bruce Berenyi | Bill Gullickson | Bruce Berenyi | | 437 | 411 | 26 |
| 1980-07-30 | vs CIN | 99 | W 2-1 | 54-45 | 2 | 28,196 | Steve Rogers | Paul Moskau | Woodie Fryman | Doug Bair | | 439 | 412 | 27 |
| 1980-08-01 | vs ATL | 100 | W 4-1 | 55-45 | 2 | 30,168 | Scott Sanderson | Phil Niekro | Scott Sanderson | Phil Niekro | | 443 | 413 | 30 |
| 1980-08-02 | vs ATL | 101 | W 5-1 | 56-45 | 1 | 41,785 | Fred Norman | Doyle Alexander | Fred Norman | Doyle Alexander | | 448 | 414 | 34 |
| 1980-08-03 | vs ATL | 102 | W 6-5 | 57-45 | 1 | 38,356 | Charlie Lea | Larry McWilliams | Charlie Lea | Larry McWilliams | Elias Sosa | 454 | 419 | 35 |
| 1980-08-04 | vs NYN | 103 | W 4-3 | 58-46 | 1 | 0 | Steve Rogers | Pat Zachry | Elias Sosa | Neil Allen | | 458 | 422 | 36 |
| 1980-08-04 | vs NYN | 104 | L 3-4 | 58-46 | 1 | 51,466 | Bill Lee | Mark Bomback | Mark Bomback | Bill Lee | Neil Allen | 461 | 426 | 35 |
| 1980-08-05 | vs NYN | 105 | W 11-5 | 59-46 | 1 | 33,821 | Bill Gullickson | John Pacella | Bill Gullickson | John Pacella | | 472 | 431 | 41 |
| 1980-08-06 | vs NYN | 106 | W 4-1 | 60-46 | 1 | 25,437 | Scott Sanderson | Roy Lee Jackson | Scott Sanderson | Roy Lee Jackson | Elias Sosa | 476 | 432 | 44 |
| 1980-08-07 | vs NYN | 107 | L 1-7 | 60-47 | 1 | 20,962 | Fred Norman | Ray Burris | Ray Burris | Fred Norman | | 477 | 439 | 38 |
| 1980-08-08 | @ CHN | 108 | W 5-2 | 61-47 | 1 | 14,706 | Charlie Lea | Mike Krukow | Charlie Lea | Mike Krukow | Woodie Fryman | 482 | 441 | 41 |
| 1980-08-09 | @ CHN | 109 | L 1-3 | 62-48 | 1 | 0 | Steve Rogers | Rick Reuschel | Rick Reuschel | Steve Rogers | Bruce Sutter | 483 | 444 | 39 |
| 1980-08-09 | @ CHN | 110 | W 4-3 | 62-48 | 1 | 28,306 | Hal Dues | Bill Caudill | Elias Sosa | Bruce Sutter | | 487 | 447 | 40 |
| 1980-08-10 | @ CHN | 111 | W 7-3 | 63-48 | 1 | 20,463 | Bill Gullickson | Dennis Lamp | Bill Gullickson | Dennis Lamp | | 494 | 450 | 44 |
| 1980-08-11 | @ SLN | 112 | L 0-16 | 63-49 | 2 | 16,647 | Scott Sanderson | Bob Sykes | Bob Sykes | Scott Sanderson | | 494 | 466 | 28 |
| 1980-08-12 | @ SLN | 113 | W 4-0 | 64-49 | 1 | 16,570 | Fred Norman | John Fulgham | Fred Norman | John Fulgham | Woodie Fryman | 498 | 466 | 32 |
| 1980-08-13 | @ SLN | 114 | L 5-7 | 64-50 | 1 | 16,187 | Charlie Lea | Bob Forsch | Bob Forsch | Hal Dues | Jim Kaat | 503 | 473 | 30 |
| 1980-08-15 | @ PIT | 115 | L 3-7 | 64-51 | 2 | 29,721 | Steve Rogers | Jim Bibby | Jim Bibby | Steve Rogers | Kent Tekulve | 506 | 480 | 26 |
| 1980-08-16 | @ PIT | 116 | L 0-5 | 64-52 | 2 | 32,390 | Scott Sanderson | Bert Blyleven | Bert Blyleven | Scott Sanderson | | 506 | 485 | 21 |
| 1980-08-17 | @ PIT | 117 | L 1-5 | 65-53 | 2 | 0 | Fred Norman | Rick Rhoden | Rick Rhoden | Fred Norman | | 507 | 490 | 17 |
| 1980-08-17 | @ PIT | 118 | W 4-2 | 65-53 | 2 | 49,412 | Bill Gullickson | Don Robinson | Bill Gullickson | Don Robinson | Woodie Fryman | 511 | 492 | 19 |
| 1980-08-19 | vs LAN | 119 | L 2-3 | 65-54 | 2 | 45,320 | Charlie Lea | Burt Hooton | Don Stanhouse | Elias Sosa | | 513 | 495 | 18 |
| 1980-08-20 | vs LAN | 120 | L 1-5 | 65-55 | 2 | 32,630 | Steve Rogers | Jerry Reuss | Jerry Reuss | Steve Rogers | | 514 | 500 | 14 |
| 1980-08-21 | vs LAN | 121 | L 4-5 | 65-56 | 3 | 33,523 | Scott Sanderson | Don Sutton | Steve Howe | Stan Bahnsen | | 518 | 505 | 13 |
| 1980-08-22 | vs SDN | 122 | W 6-2 | 66-56 | 2 | 26,443 | Fred Norman | Randy Jones | Fred Norman | Randy Jones | | 524 | 507 | 17 |
| 1980-08-23 | vs SDN | 123 | W 2-0 | 67-56 | 2 | 41,354 | Bill Gullickson | Steve Mura | Bill Gullickson | Steve Mura | John D'Acquisto | 526 | 507 | 19 |
| 1980-08-24 | vs SDN | 124 | W 12-9 | 68-56 | 2 | 37,650 | Charlie Lea | Bob Shirley | Elias Sosa | Rollie Fingers | John D'Acquisto | 538 | 516 | 22 |
| 1980-08-25 | vs SFN | 125 | W 3-1 | 69-56 | 2 | 32,602 | Steve Rogers | Alan Hargesheimer | Steve Rogers | Alan Hargesheimer | | 541 | 517 | 24 |
| 1980-08-27 | vs SFN | 126 | L 0-1 | 69-57 | 2 | 24,294 | Scott Sanderson | Ed Whitson | Ed Whitson | Scott Sanderson | Greg Minton | 541 | 518 | 23 |
| 1980-08-29 | @ LAN | 127 | L 4-5 | 69-58 | 1 | 50,810 | Fred Norman | Dave Goltz | Bobby Castillo | John D'Acquisto | Steve Howe | 545 | 523 | 22 |
| 1980-08-30 | @ LAN | 128 | L 3-4 | 69-59 | 1 | 35,778 | Bill Gullickson | Burt Hooton | Burt Hooton | Bill Gullickson | Don Stanhouse | 548 | 527 | 21 |
| 1980-08-31 | @ LAN | 129 | L 0-2 | 69-61 | 3 | 0 | Steve Rogers | Jerry Reuss | Jerry Reuss | Steve Rogers | | 548 | 529 | 19 |
| 1980-08-31 | @ LAN | 130 | L 2-7 | 69-61 | 3 | 48,542 | David Palmer | Don Sutton | Don Sutton | David Palmer | | 550 | 536 | 14 |
| 1980-09-01 | @ SDN | 131 | W 5-3 | 70-61 | 2 | 9,385 | Scott Sanderson | Rick Wise | Scott Sanderson | Rick Wise | Woodie Fryman | 555 | 539 | 16 |
| 1980-09-02 | @ SDN | 132 | W 2-1 | 71-61 | 2 | 6,082 | Charlie Lea | Eric Rasmussen | Charlie Lea | Eric Rasmussen | Woodie Fryman | 557 | 540 | 17 |
| 1980-09-03 | @ SDN | 133 | L 3-4 | 71-62 | 3 | 6,685 | Fred Norman | Steve Mura | Steve Mura | Fred Norman | Rollie Fingers | 560 | 544 | 16 |
| 1980-09-04 | @ SFN | 134 | W 4-0 | 72-62 | 2 | 4,038 | Bill Gullickson | Alan Hargesheimer | Bill Gullickson | Alan Hargesheimer | | 564 | 544 | 20 |
| 1980-09-05 | @ SFN | 135 | W 8-0 | 73-62 | 2 | 7,698 | Steve Rogers | John Montefusco | Steve Rogers | John Montefusco | | 572 | 544 | 28 |
| 1980-09-06 | @ SFN | 136 | W 9-0 | 74-62 | 1 | 6,653 | Scott Sanderson | Ed Whitson | Scott Sanderson | Ed Whitson | | 581 | 544 | 37 |
| 1980-09-07 | @ SFN | 137 | L 3-6 | 74-63 | 1 | 8,314 | Charlie Lea | Vida Blue | Vida Blue | John D'Acquisto | Greg Minton | 584 | 550 | 34 |
| 1980-09-09 | vs NYN | 138 | W 3-0 | 75-63 | 1 | 27,659 | Steve Rogers | Pat Zachry | Steve Rogers | Pat Zachry | | 587 | 550 | 37 |
| 1980-09-10 | vs CHN | 139 | W 4-2 | 76-63 | 1 | 17,874 | Bill Gullickson | Rick Reuschel | Bill Gullickson | Rick Reuschel | | 591 | 552 | 39 |
| 1980-09-11 | vs CHN | 140 | W 6-5 | 77-63 | 1 | 24,703 | Charlie Lea | Randy Martz | Woodie Fryman | Randy Martz | | 597 | 557 | 40 |
| 1980-09-12 | vs PIT | 141 | W 1-0 | 78-63 | 1 | 36,992 | Scott Sanderson | Rick Rhoden | Scott Sanderson | Rick Rhoden | | 598 | 557 | 41 |
| 1980-09-13 | vs PIT | 142 | L 0-4 | 78-64 | 1 | 51,305 | Steve Rogers | Don Robinson | Don Robinson | Steve Rogers | | 598 | 561 | 37 |
| 1980-09-14 | vs PIT | 143 | W 4-0 | 79-64 | 1 | 56,137 | Bill Gullickson | John Candelaria | Bill Gullickson | John Candelaria | | 602 | 561 | 41 |
| 1980-09-16 | @ NYN | 144 | W 5-3 | 81-64 | 1 | 0 | Charlie Lea | Ray Burris | Elias Sosa | Juan Berenguer | | 607 | 564 | 43 |
| 1980-09-16 | @ NYN | 145 | W 4-2 | 81-64 | 1 | 5,832 | David Palmer | Mark Bomback | David Palmer | Roy Lee Jackson | Stan Bahnsen | 611 | 566 | 45 |
| 1980-09-17 | @ NYN | 146 | L 2-5 | 81-65 | 1 | 5,723 | Scott Sanderson | Mike Scott | Dyar Miller | Scott Sanderson | Pete Falcone | 613 | 571 | 42 |
| 1980-09-19 | @ SLN | 147 | L 8-9 | 81-66 | 1 | 10,251 | Steve Rogers | Bob Forsch | Jim Kaat | Elias Sosa | | 621 | 580 | 41 |
| 1980-09-20 | @ SLN | 148 | W 5-4 | 82-66 | 1 | 10,916 | Bill Gullickson | Al Olmsted | Bill Lee | John Littlefield | | 626 | 584 | 42 |
| 1980-09-21 | @ SLN | 149 | L 1-4 | 82-67 | 1 | 10,068 | David Palmer | Andy Rincon | Andy Rincon | David Palmer | Kim Seaman | 627 | 588 | 39 |
| 1980-09-22 | @ PIT | 150 | L 2-4 | 82-68 | 2 | 18,416 | Scott Sanderson | Jim Bibby | Jim Bibby | Scott Sanderson | Kent Tekulve | 629 | 592 | 37 |
| 1980-09-23 | @ PIT | 151 | W 7-1 | 83-68 | 1 | 26,729 | Steve Rogers | Bert Blyleven | Steve Rogers | Bert Blyleven | | 636 | 593 | 43 |
| 1980-09-24 | @ CHN | 152 | W 8-4 | 84-68 | 1 | 2,915 | Charlie Lea | Rick Reuschel | Charlie Lea | Rick Reuschel | Stan Bahnsen | 644 | 597 | 47 |
| 1980-09-25 | @ CHN | 153 | L 4-5 | 84-69 | 2 | 2,660 | Bill Gullickson | Lynn McGlothen | Lynn McGlothen | Bill Gullickson | Dick Tidrow | 648 | 602 | 46 |
| 1980-09-26 | @ PHI | 154 | L 1-2 | 84-70 | 2 | 50,887 | David Palmer | Dick Ruthven | Tug McGraw | David Palmer | | 649 | 604 | 45 |
| 1980-09-27 | @ PHI | 155 | W 4-3 | 85-70 | 2 | 53,058 | Scott Sanderson | Steve Carlton | Scott Sanderson | Steve Carlton | Woodie Fryman | 653 | 607 | 46 |
| 1980-09-28 | @ PHI | 156 | W 8-3 | 86-70 | 1 | 40,305 | Steve Rogers | Bob Walk | Steve Rogers | Bob Walk | | 661 | 610 | 51 |
| 1980-09-29 | vs SLN | 157 | W 5-2 | 87-70 | 1 | 34,064 | Bill Lee | Pete Vuckovich | Woodie Fryman | George Frazier | | 666 | 612 | 54 |
| 1980-09-30 | vs SLN | 158 | W 7-2 | 88-70 | 1 | 30,759 | Bill Gullickson | Bob Forsch | Bill Gullickson | Bob Forsch | | 673 | 614 | 59 |
| 1980-10-01 | vs SLN | 159 | W 8-0 | 89-70 | 1 | 20,063 | David Palmer | Andy Rincon | David Palmer | Andy Rincon | | 681 | 614 | 67 |
| 1980-10-03 | vs PHI | 160 | L 1-2 | 89-71 | 2 | 57,121 | Scott Sanderson | Dick Ruthven | Dick Ruthven | Scott Sanderson | Tug McGraw | 682 | 616 | 66 |
| 1980-10-04 | vs PHI | 161 | L 4-6 | 89-72 | 2 | 50,794 | Steve Rogers | Larry Christenson | Tug McGraw | Stan Bahnsen | | 686 | 622 | 64 |
| 1980-10-05 | vs PHI | 162 | W 8-7 | 90-72 | 2 | 30,104 | Steve Ratzer | Mark Davis | Charlie Lea | Warren Brusstar | | 694 | 629 | 65 |