| 1980-04-10 | vs LAN | 1 | W 3-2 | - | | 33,270 | J.R. Richard | Burt Hooton | J.R. Richard | Burt Hooton | Joe Sambito | 3 | 2 | 1 |
| 1980-04-11 | vs LAN | 2 | W 10-6 | - | | 30,701 | Joe Niekro | Rick Sutcliffe | Dave Smith | Don Stanhouse | | 13 | 8 | 5 |
| 1980-04-12 | vs LAN | 3 | L 5-6 | - | | 24,609 | Nolan Ryan | Don Sutton | Steve Howe | Dave Smith | Burt Hooton | 18 | 14 | 4 |
| 1980-04-13 | vs LAN | 4 | W 4-2 | - | | 33,676 | Ken Forsch | Dave Goltz | Ken Forsch | Dave Goltz | Frank LaCorte | 22 | 16 | 6 |
| 1980-04-14 | vs ATL | 5 | W 5-4 | - | | 15,017 | J.R. Richard | Doyle Alexander | Joe Sambito | Gene Garber | | 27 | 20 | 7 |
| 1980-04-15 | vs ATL | 6 | W 6-2 | - | | 15,712 | Joe Niekro | Larry McWilliams | Joe Niekro | Larry McWilliams | | 33 | 22 | 11 |
| 1980-04-17 | @ LAN | 7 | L 4-6 | - | | 45,476 | Nolan Ryan | Don Sutton | Jerry Reuss | Dave Smith | | 37 | 28 | 9 |
| 1980-04-18 | @ LAN | 8 | W 7-4 | - | | 41,112 | Ken Forsch | Dave Goltz | Ken Forsch | Dave Goltz | Joaquin Andujar | 44 | 32 | 12 |
| 1980-04-19 | @ LAN | 9 | W 2-0 | - | | 50,112 | J.R. Richard | Bob Welch | J.R. Richard | Bob Welch | | 46 | 32 | 14 |
| 1980-04-20 | @ LAN | 10 | L 2-4 | - | | 39,442 | Joe Niekro | Rick Sutcliffe | Jerry Reuss | Joe Niekro | | 48 | 36 | 12 |
| 1980-04-21 | vs CIN | 11 | L 5-6 | - | | 29,067 | Vern Ruhle | Mike LaCoss | Mike LaCoss | Vern Ruhle | Tom Hume | 53 | 42 | 11 |
| 1980-04-22 | vs CIN | 12 | W 8-0 | - | | 30,094 | Nolan Ryan | Frank Pastore | Nolan Ryan | Frank Pastore | | 61 | 42 | 19 |
| 1980-04-23 | vs CIN | 13 | L 2-3 | - | | 29,828 | Ken Forsch | Charlie Leibrandt | Tom Hume | Joaquin Andujar | Doug Bair | 63 | 45 | 18 |
| 1980-04-25 | vs NYN | 14 | W 7-4 | - | | 24,140 | J.R. Richard | Pete Falcone | J.R. Richard | Pete Falcone | | 70 | 49 | 21 |
| 1980-04-26 | vs NYN | 15 | W 6-0 | - | | 44,540 | Joe Niekro | Craig Swan | Joe Niekro | Ed Glynn | Frank LaCorte | 76 | 49 | 27 |
| 1980-04-27 | vs NYN | 16 | W 4-3 | - | | 20,828 | Nolan Ryan | Ray Burris | Frank LaCorte | Neil Allen | | 80 | 52 | 28 |
| 1980-04-29 | @ CIN | 17 | W 3-0 | - | | 18,092 | Ken Forsch | Charlie Leibrandt | Ken Forsch | Charlie Leibrandt | | 83 | 52 | 31 |
| 1980-04-30 | @ CIN | 18 | W 5-1 | - | | 19,821 | J.R. Richard | Tom Seaver | J.R. Richard | Tom Seaver | | 88 | 53 | 35 |
| 1980-05-01 | @ CIN | 19 | W 9-3 | - | | 18,215 | Joe Niekro | Mike LaCoss | Joe Niekro | Mike LaCoss | | 97 | 56 | 41 |
| 1980-05-02 | @ SLN | 20 | L 1-9 | - | | 23,009 | Nolan Ryan | Bob Forsch | Don Hood | Nolan Ryan | Jim Kaat | 98 | 65 | 33 |
| 1980-05-03 | @ SLN | 21 | W 4-2 | - | | 23,292 | Vern Ruhle | Silvio Martinez | Vern Ruhle | Silvio Martinez | Joe Sambito | 102 | 67 | 35 |
| 1980-05-04 | @ SLN | 22 | W 4-2 | - | | 17,262 | Ken Forsch | Bob Sykes | Ken Forsch | Bob Sykes | Frank LaCorte | 106 | 69 | 37 |
| 1980-05-05 | @ MON | 23 | L 1-10 | - | | 5,477 | J.R. Richard | David Palmer | David Palmer | J.R. Richard | | 107 | 79 | 28 |
| 1980-05-06 | @ MON | 24 | W 8-4 | - | | 5,503 | Joe Niekro | Ross Grimsley | Joe Niekro | Ross Grimsley | | 115 | 83 | 32 |
| 1980-05-07 | @ MON | 25 | L 0-3 | - | | 7,386 | Nolan Ryan | Scott Sanderson | Scott Sanderson | Nolan Ryan | Woodie Fryman | 115 | 86 | 29 |
| 1980-05-09 | @ ATL | 26 | L 4-5 | - | | 11,111 | Ken Forsch | Larry McWilliams | Larry McWilliams | Ken Forsch | Larry Bradford | 119 | 91 | 28 |
| 1980-05-10 | @ ATL | 27 | W 3-2 | - | | 13,798 | J.R. Richard | Rick Matula | Frank LaCorte | Gene Garber | Joe Sambito | 122 | 93 | 29 |
| 1980-05-11 | @ ATL | 28 | L 4-7 | - | | 10,871 | Joe Niekro | Phil Niekro | Phil Niekro | Joe Niekro | | 126 | 100 | 26 |
| 1980-05-13 | vs MON | 29 | L 2-3 | - | | 24,835 | Nolan Ryan | David Palmer | David Palmer | Nolan Ryan | Woodie Fryman | 128 | 103 | 25 |
| 1980-05-14 | vs MON | 30 | L 0-1 | - | | 20,636 | Ken Forsch | Scott Sanderson | Scott Sanderson | Ken Forsch | Woodie Fryman | 128 | 104 | 24 |
| 1980-05-16 | vs PHI | 31 | L 0-3 | - | | 33,610 | J.R. Richard | Dick Ruthven | Dick Ruthven | J.R. Richard | | 128 | 107 | 21 |
| 1980-05-17 | vs PHI | 32 | L 2-4 | - | | 43,525 | Joe Niekro | Larry Christenson | Larry Christenson | Joe Niekro | Dickie Noles | 130 | 111 | 19 |
| 1980-05-18 | vs PHI | 33 | W 3-0 | - | | 33,950 | Nolan Ryan | Randy Lerch | Nolan Ryan | Randy Lerch | | 133 | 111 | 22 |
| 1980-05-20 | @ NYN | 34 | W 3-2 | - | | 8,466 | Ken Forsch | Craig Swan | Ken Forsch | Craig Swan | | 136 | 113 | 23 |
| 1980-05-21 | @ NYN | 35 | L 1-5 | - | | 4,233 | J.R. Richard | Pete Falcone | Pete Falcone | J.R. Richard | Neil Allen | 137 | 118 | 19 |
| 1980-05-22 | @ NYN | 36 | W 8-5 | - | | 7,812 | Joe Niekro | Mark Bomback | Joe Niekro | Kevin Kobel | Frank LaCorte | 145 | 123 | 22 |
| 1980-05-23 | @ PHI | 37 | L 0-3 | - | | 27,822 | Nolan Ryan | Steve Carlton | Steve Carlton | Nolan Ryan | | 145 | 126 | 19 |
| 1980-05-24 | @ PHI | 38 | L 4-5 | - | | 28,539 | Joaquin Andujar | Dan Larson | Kevin Saucier | Joaquin Andujar | Tug McGraw | 149 | 131 | 18 |
| 1980-05-25 | @ PHI | 39 | L 2-6 | - | | 37,349 | Ken Forsch | Dick Ruthven | Dick Ruthven | Ken Forsch | | 151 | 137 | 14 |
| 1980-05-26 | vs SDN | 40 | W 4-1 | - | | 18,242 | J.R. Richard | John Curtis | J.R. Richard | John Curtis | Joe Sambito | 155 | 138 | 17 |
| 1980-05-27 | vs SDN | 41 | W 4-3 | - | | 18,246 | Joe Niekro | Gary Lucas | Frank LaCorte | Rollie Fingers | | 159 | 141 | 18 |
| 1980-05-28 | vs SDN | 42 | W 1-0 | - | | 19,697 | Nolan Ryan | Rick Wise | Nolan Ryan | Rick Wise | | 160 | 141 | 19 |
| 1980-05-30 | @ SFN | 43 | L 2-3 | - | | 10,511 | Ken Forsch | Vida Blue | Vida Blue | Ken Forsch | | 162 | 144 | 18 |
| 1980-05-31 | @ SFN | 44 | W 5-0 | - | | 11,649 | J.R. Richard | John Montefusco | J.R. Richard | John Montefusco | | 167 | 144 | 23 |
| 1980-06-01 | @ SFN | 45 | L 2-6 | - | | 19,801 | Joe Niekro | Bob Knepper | Bob Knepper | Joe Niekro | | 169 | 150 | 19 |
| 1980-06-02 | @ SDN | 46 | L 0-3 | - | | 27,176 | Nolan Ryan | Rick Wise | Rick Wise | Nolan Ryan | Eric Rasmussen | 169 | 153 | 16 |
| 1980-06-03 | @ SDN | 47 | W 3-2 | - | | 12,363 | Vern Ruhle | Randy Jones | Vern Ruhle | Randy Jones | Frank LaCorte | 172 | 155 | 17 |
| 1980-06-04 | @ SDN | 48 | W 4-3 | - | | 13,619 | Ken Forsch | Steve Mura | Ken Forsch | Rollie Fingers | Joe Sambito | 176 | 158 | 18 |
| 1980-06-06 | vs SFN | 49 | W 2-0 | - | | 26,822 | J.R. Richard | Bob Knepper | J.R. Richard | Bob Knepper | | 178 | 158 | 20 |
| 1980-06-07 | vs SFN | 50 | W 3-0 | - | | 42,263 | Joe Niekro | Ed Whitson | Joe Niekro | Ed Whitson | | 181 | 158 | 23 |
| 1980-06-08 | vs SFN | 51 | W 5-4 | - | | 28,327 | Nolan Ryan | Vida Blue | Joe Sambito | Greg Minton | | 186 | 162 | 24 |
| 1980-06-09 | vs CHN | 52 | W 6-2 | - | | 19,022 | Ken Forsch | Dennis Lamp | Ken Forsch | Dennis Lamp | | 192 | 164 | 28 |
| 1980-06-10 | vs CHN | 53 | W 5-2 | - | | 22,201 | Vern Ruhle | Mike Krukow | Vern Ruhle | Mike Krukow | | 197 | 166 | 31 |
| 1980-06-11 | vs CHN | 54 | W 3-0 | - | | 31,599 | J.R. Richard | Rick Reuschel | J.R. Richard | Rick Reuschel | | 200 | 166 | 34 |
| 1980-06-13 | @ PIT | 55 | L 3-5 | - | | 31,854 | Joe Niekro | Eddie Solomon | Eddie Solomon | Joe Niekro | Kent Tekulve | 203 | 171 | 32 |
| 1980-06-14 | @ PIT | 56 | W 7-3 | - | | 33,922 | Nolan Ryan | Don Robinson | Nolan Ryan | Don Robinson | Frank LaCorte | 210 | 174 | 36 |
| 1980-06-15 | @ PIT | 57 | L 1-4 | - | | 49,541 | Ken Forsch | John Candelaria | John Candelaria | Ken Forsch | | 211 | 178 | 33 |
| 1980-06-16 | @ CHN | 58 | W 2-1 | - | | 15,289 | Vern Ruhle | Rick Reuschel | Vern Ruhle | Guillermo Hernandez | Dave Smith | 213 | 179 | 34 |
| 1980-06-17 | @ CHN | 59 | W 7-1 | - | | 19,480 | J.R. Richard | Lynn McGlothen | J.R. Richard | Lynn McGlothen | Joaquin Andujar | 220 | 180 | 40 |
| 1980-06-18 | vs SLN | 60 | W 3-0 | - | | 24,459 | Joe Niekro | Jim Kaat | Joe Niekro | Jim Kaat | | 223 | 180 | 43 |
| 1980-06-19 | vs SLN | 61 | W 2-0 | - | | 24,663 | Nolan Ryan | Bob Sykes | Nolan Ryan | Bob Sykes | Joe Sambito | 225 | 180 | 45 |
| 1980-06-20 | vs PIT | 62 | W 6-4 | - | | 35,955 | Ken Forsch | John Candelaria | Ken Forsch | John Candelaria | Joe Sambito | 231 | 184 | 47 |
| 1980-06-21 | vs PIT | 63 | W 4-2 | - | | 45,867 | Vern Ruhle | Bert Blyleven | Vern Ruhle | Bert Blyleven | Joe Sambito | 235 | 186 | 49 |
| 1980-06-22 | vs PIT | 64 | L 1-2 | - | | 46,213 | Joe Niekro | Jim Bibby | Jim Bibby | Joe Niekro | Grant Jackson | 236 | 188 | 48 |
| 1980-06-23 | vs LAN | 65 | L 0-3 | - | | 29,753 | Joaquin Andujar | Rick Sutcliffe | Rick Sutcliffe | Joaquin Andujar | | 236 | 191 | 45 |
| 1980-06-24 | vs LAN | 66 | W 5-4 | - | | 34,388 | Nolan Ryan | Burt Hooton | Frank LaCorte | Joe Beckwith | | 241 | 195 | 46 |
| 1980-06-25 | vs LAN | 67 | L 2-9 | - | | 34,416 | Ken Forsch | Bob Welch | Bob Welch | Ken Forsch | | 243 | 204 | 39 |
| 1980-06-27 | vs CIN | 68 | W 5-4 | - | | 36,648 | Joe Niekro | Frank Pastore | Joe Niekro | Frank Pastore | Joe Sambito | 248 | 208 | 40 |
| 1980-06-28 | vs CIN | 69 | L 5-8 | - | | 44,025 | J.R. Richard | Joe Price | Joe Price | J.R. Richard | Tom Hume | 253 | 216 | 37 |
| 1980-06-29 | vs CIN | 70 | W 12-10 | - | | 38,408 | Nolan Ryan | Charlie Leibrandt | Frank LaCorte | Mario Soto | Joe Sambito | 265 | 226 | 39 |
| 1980-06-30 | @ ATL | 71 | L 4-5 | - | | 8,208 | Ken Forsch | Rick Matula | Al Hrabosky | Joe Sambito | | 269 | 231 | 38 |
| 1980-07-01 | @ ATL | 72 | L 4-13 | - | | 9,546 | Joe Niekro | Doyle Alexander | Doyle Alexander | Joe Niekro | | 273 | 244 | 29 |
| 1980-07-02 | @ ATL | 73 | L 0-14 | - | | 21,908 | Vern Ruhle | Phil Niekro | Phil Niekro | Vern Ruhle | | 273 | 258 | 15 |
| 1980-07-03 | @ ATL | 74 | W 5-3 | - | | 15,769 | J.R. Richard | Tommy Boggs | J.R. Richard | Tommy Boggs | Frank LaCorte | 278 | 261 | 17 |
| 1980-07-04 | @ CIN | 75 | L 1-8 | - | | 37,047 | Nolan Ryan | Charlie Leibrandt | Charlie Leibrandt | Nolan Ryan | | 279 | 269 | 10 |
| 1980-07-05 | @ CIN | 76 | L 6-8 | - | | 0 | Ken Forsch | Bruce Berenyi | Mario Soto | Ken Forsch | | 285 | 277 | 8 |
| 1980-07-05 | @ CIN | 77 | L 2-3 | - | | 44,083 | Joaquin Andujar | Mike LaCoss | Mike LaCoss | Joaquin Andujar | Tom Hume | 287 | 280 | 7 |
| 1980-07-06 | @ CIN | 78 | W 3-2 | - | | 30,045 | Joe Niekro | Frank Pastore | Joe Niekro | Frank Pastore | Frank LaCorte | 290 | 282 | 8 |
| 1980-07-10 | @ LAN | 79 | L 3-4 | - | | 49,692 | Nolan Ryan | Burt Hooton | Steve Howe | Nolan Ryan | | 293 | 286 | 7 |
| 1980-07-11 | @ LAN | 80 | L 2-3 | - | | 42,754 | Ken Forsch | Jerry Reuss | Jerry Reuss | Ken Forsch | Steve Howe | 295 | 289 | 6 |
| 1980-07-12 | vs ATL | 81 | W 9-5 | - | | 38,610 | Joe Niekro | Larry McWilliams | Joe Niekro | Larry McWilliams | Dave Smith | 304 | 294 | 10 |
| 1980-07-13 | vs ATL | 82 | W 6-5 | - | | 0 | Joaquin Andujar | Rick Matula | Joe Sambito | Gene Garber | Frank LaCorte | 310 | 299 | 11 |
| 1980-07-13 | vs ATL | 83 | W 6-1 | - | | 31,230 | Vern Ruhle | Tommy Boggs | Vern Ruhle | Tommy Boggs | | 316 | 300 | 16 |
| 1980-07-14 | vs ATL | 84 | L 0-2 | - | | 20,247 | J.R. Richard | Phil Niekro | Phil Niekro | Gordie Pladson | | 316 | 302 | 14 |
| 1980-07-15 | vs PHI | 85 | W 3-2 | - | | 24,223 | Nolan Ryan | Dick Ruthven | Joe Sambito | Dick Ruthven | | 319 | 304 | 15 |
| 1980-07-16 | vs PHI | 86 | L 2-4 | - | | 28,532 | Ken Forsch | Bob Walk | Bob Walk | Ken Forsch | | 321 | 308 | 13 |
| 1980-07-17 | vs PHI | 87 | L 1-2 | - | | 26,403 | Joe Niekro | Steve Carlton | Steve Carlton | Joe Niekro | | 322 | 310 | 12 |
| 1980-07-18 | vs MON | 88 | L 4-5 | - | | 26,389 | Vern Ruhle | Bill Lee | Woodie Fryman | Dave Smith | Fred Norman | 326 | 315 | 11 |
| 1980-07-19 | vs MON | 89 | W 4-2 | - | | 40,499 | Joaquin Andujar | Charlie Lea | Joaquin Andujar | Charlie Lea | Dave Smith | 330 | 317 | 13 |
| 1980-07-19 | vs MON | 90 | L 2-5 | - | | 39,507 | Gordie Pladson | Bill Gullickson | Bill Gullickson | Gordie Pladson | | 332 | 322 | 10 |
| 1980-07-20 | vs MON | 91 | W 4-3 | - | | 28,513 | Nolan Ryan | Steve Rogers | Joe Sambito | Fred Norman | | 336 | 325 | 11 |
| 1980-07-21 | vs NYN | 92 | W 3-2 | - | | 20,548 | Ken Forsch | Tom Hausman | Frank LaCorte | Neil Allen | | 339 | 327 | 12 |
| 1980-07-22 | vs NYN | 93 | W 6-5 | - | | 26,815 | Joe Niekro | John Pacella | Bert Roberge | Ed Glynn | Dave Smith | 345 | 332 | 13 |
| 1980-07-23 | vs NYN | 94 | L 3-4 | - | | 30,236 | Vern Ruhle | Pete Falcone | Jeff Reardon | Frank LaCorte | Neil Allen | 348 | 336 | 12 |
| 1980-07-25 | @ MON | 95 | W 9-8 | - | | 50,217 | Nolan Ryan | Steve Rogers | Frank LaCorte | Elias Sosa | | 357 | 344 | 13 |
| 1980-07-26 | @ MON | 96 | L 1-2 | - | | 42,400 | Ken Forsch | Scott Sanderson | Stan Bahnsen | Frank LaCorte | | 358 | 346 | 12 |
| 1980-07-27 | @ MON | 97 | W 6-3 | - | | 41,107 | Joe Niekro | Bill Lee | Joe Niekro | Bill Lee | Dave Smith | 364 | 349 | 15 |
| 1980-07-28 | @ PHI | 98 | W 3-2 | - | | 30,181 | Gordie Pladson | Nino Espinosa | Joe Sambito | Ron Reed | | 367 | 351 | 16 |
| 1980-07-29 | @ PHI | 99 | L 6-9 | - | | 30,252 | Joaquin Andujar | Randy Lerch | Kevin Saucier | Frank LaCorte | Tug McGraw | 373 | 360 | 13 |
| 1980-07-30 | @ PHI | 100 | L 4-6 | - | | 31,342 | Nolan Ryan | Dick Ruthven | Dick Ruthven | Nolan Ryan | Tug McGraw | 377 | 366 | 11 |
| 1980-08-01 | @ NYN | 101 | L 4-5 | - | | 16,612 | Ken Forsch | John Pacella | Jeff Reardon | Dave Smith | | 381 | 371 | 10 |
| 1980-08-02 | @ NYN | 102 | L 3-5 | - | | 45,426 | Joe Niekro | Roy Lee Jackson | Neil Allen | Joe Niekro | | 384 | 376 | 8 |
| 1980-08-03 | @ NYN | 103 | W 3-2 | - | | 22,492 | Vern Ruhle | Pete Falcone | Joe Sambito | Jeff Reardon | | 387 | 378 | 9 |
| 1980-08-04 | vs SFN | 104 | W 4-2 | - | | 27,040 | Nolan Ryan | Alan Hargesheimer | Nolan Ryan | Alan Hargesheimer | Joe Sambito | 391 | 380 | 11 |
| 1980-08-05 | vs SFN | 105 | L 3-9 | - | | 24,198 | Gordie Pladson | Jeff Stember | Gary Lavelle | Gordie Pladson | | 394 | 389 | 5 |
| 1980-08-06 | vs SFN | 106 | W 1-0 | - | | 23,478 | Ken Forsch | Vida Blue | Ken Forsch | Vida Blue | | 395 | 389 | 6 |
| 1980-08-07 | vs SDN | 107 | L 1-5 | - | | 20,044 | Joe Niekro | Bob Shirley | Bob Shirley | Joe Niekro | | 396 | 394 | 2 |
| 1980-08-08 | vs SDN | 108 | L 3-5 | - | | 15,207 | Vern Ruhle | Randy Jones | Juan Eichelberger | Joe Sambito | Rollie Fingers | 399 | 399 | 0 |
| 1980-08-09 | vs SDN | 109 | W 9-5 | - | | 21,233 | Nolan Ryan | John Curtis | Dave Smith | John D'Acquisto | | 408 | 404 | 4 |
| 1980-08-10 | vs SDN | 110 | L 2-3 | - | | 20,514 | Joaquin Andujar | Rick Wise | Rick Wise | Joe Sambito | | 410 | 407 | 3 |
| 1980-08-11 | @ SFN | 111 | L 4-5 | - | | 10,755 | Ken Forsch | Vida Blue | Vida Blue | Ken Forsch | Greg Minton | 414 | 412 | 2 |
| 1980-08-12 | @ SFN | 112 | L 0-2 | - | | 29,770 | Joe Niekro | Allen Ripley | Allen Ripley | Joe Niekro | Gary Lavelle | 414 | 414 | 0 |
| 1980-08-13 | @ SFN | 113 | L 5-6 | - | | 10,149 | Vern Ruhle | Bob Knepper | Mike Rowland | Dave Smith | | 419 | 420 | -1 |
| 1980-08-14 | @ SDN | 114 | W 2-1 | - | | 12,150 | Nolan Ryan | John Curtis | Nolan Ryan | John Curtis | | 421 | 421 | 0 |
| 1980-08-15 | @ SDN | 115 | W 3-1 | - | | 14,177 | Gordie Pladson | Rick Wise | Dave Smith | Eric Rasmussen | | 424 | 422 | 2 |
| 1980-08-17 | @ SDN | 116 | W 5-0 | - | | 0 | Ken Forsch | Randy Jones | Ken Forsch | Randy Jones | | 429 | 422 | 7 |
| 1980-08-17 | @ SDN | 117 | W 9-2 | - | | 16,120 | Joe Niekro | Steve Mura | Joe Niekro | Steve Mura | | 438 | 424 | 14 |
| 1980-08-19 | vs PIT | 118 | W 5-2 | - | | 39,415 | Nolan Ryan | John Candelaria | Nolan Ryan | John Candelaria | Joe Sambito | 443 | 426 | 17 |
| 1980-08-20 | vs PIT | 119 | W 5-1 | - | | 32,112 | Vern Ruhle | Jim Bibby | Vern Ruhle | Jim Bibby | Dave Smith | 448 | 427 | 21 |
| 1980-08-21 | vs PIT | 120 | W 12-5 | - | | 33,884 | Joe Niekro | Bert Blyleven | Joe Sambito | Bert Blyleven | | 460 | 432 | 28 |
| 1980-08-22 | vs CHN | 121 | W 3-2 | - | | 34,118 | Gordie Pladson | Rick Reuschel | Frank LaCorte | Bill Caudill | | 463 | 434 | 29 |
| 1980-08-23 | vs CHN | 122 | W 1-0 | - | | 25,031 | Joaquin Andujar | Dennis Lamp | Joe Niekro | George Riley | | 464 | 434 | 30 |
| 1980-08-24 | vs CHN | 123 | W 2-1 | - | | 25,703 | Nolan Ryan | Doug Capilla | Nolan Ryan | Bill Caudill | | 466 | 435 | 31 |
| 1980-08-25 | @ SLN | 124 | L 1-3 | - | | 9,185 | Vern Ruhle | Don Hood | Don Hood | Vern Ruhle | | 467 | 438 | 29 |
| 1980-08-26 | @ SLN | 125 | W 7-2 | - | | 10,859 | Joe Niekro | Jim Kaat | Joe Niekro | Jim Kaat | | 474 | 440 | 34 |
| 1980-08-27 | @ SLN | 126 | L 2-10 | - | | 10,025 | Ken Forsch | John Fulgham | John Martin | Ken Forsch | | 476 | 450 | 26 |
| 1980-08-28 | @ CHN | 127 | W 4-1 | - | | 18,694 | Joaquin Andujar | Dennis Lamp | Joaquin Andujar | Dennis Lamp | Joe Sambito | 480 | 451 | 29 |
| 1980-08-29 | @ CHN | 128 | W 6-5 | - | | 9,994 | Nolan Ryan | Mike Krukow | Dave Smith | Dick Tidrow | Frank LaCorte | 486 | 456 | 30 |
| 1980-08-30 | @ CHN | 129 | W 2-0 | - | | 18,803 | Vern Ruhle | Lynn McGlothen | Vern Ruhle | Lynn McGlothen | | 488 | 456 | 32 |
| 1980-08-31 | @ CHN | 130 | L 7-8 | - | | 14,823 | Joe Niekro | Rick Reuschel | Dick Tidrow | Frank LaCorte | | 495 | 464 | 31 |
| 1980-09-01 | @ PIT | 131 | W 10-4 | - | | 0 | Ken Forsch | Don Robinson | Dave Smith | Don Robinson | | 505 | 468 | 37 |
| 1980-09-01 | @ PIT | 132 | L 5-7 | - | | 26,374 | Gordie Pladson | Rick Rhoden | Rick Rhoden | Gordie Pladson | Grant Jackson | 510 | 475 | 35 |
| 1980-09-03 | @ PIT | 133 | L 4-10 | - | | 18,502 | Joaquin Andujar | John Candelaria | John Candelaria | Joaquin Andujar | Enrique Romo | 514 | 485 | 29 |
| 1980-09-05 | vs SLN | 134 | L 5-7 | - | | 19,628 | Nolan Ryan | Don Hood | Kim Seaman | Joe Sambito | George Frazier | 519 | 492 | 27 |
| 1980-09-06 | vs SLN | 135 | W 9-5 | - | | 0 | Joe Niekro | Bob Sykes | Joe Niekro | Bob Sykes | Randy Niemann | 528 | 497 | 31 |
| 1980-09-06 | vs SLN | 136 | W 6-4 | - | | 34,350 | Vern Ruhle | John Martin | Vern Ruhle | John Martin | | 534 | 501 | 33 |
| 1980-09-07 | vs SLN | 137 | L 0-2 | - | | 16,475 | Ken Forsch | Pete Vuckovich | Pete Vuckovich | Ken Forsch | | 534 | 503 | 31 |
| 1980-09-09 | vs LAN | 138 | W 5-4 | - | | 34,546 | Joaquin Andujar | Jerry Reuss | Dave Smith | Steve Howe | Joe Sambito | 539 | 507 | 32 |
| 1980-09-10 | vs LAN | 139 | W 6-5 | - | | 37,632 | Nolan Ryan | Burt Hooton | Bert Roberge | Rick Sutcliffe | | 545 | 512 | 33 |
| 1980-09-12 | vs SFN | 140 | W 5-3 | - | | 23,380 | Joe Niekro | Ed Whitson | Joe Niekro | Ed Whitson | Dave Smith | 550 | 515 | 35 |
| 1980-09-13 | vs SFN | 141 | W 3-2 | - | | 32,526 | Ken Forsch | Vida Blue | Ken Forsch | Vida Blue | | 553 | 517 | 36 |
| 1980-09-14 | vs SFN | 142 | W 6-4 | - | | 18,471 | Joaquin Andujar | John Montefusco | Joaquin Andujar | John Montefusco | Joe Sambito | 559 | 521 | 38 |
| 1980-09-15 | vs SDN | 143 | L 3-6 | - | | 9,578 | Nolan Ryan | Bob Shirley | Bob Shirley | Nolan Ryan | | 562 | 527 | 35 |
| 1980-09-16 | vs SDN | 144 | L 3-4 | - | | 20,383 | Vern Ruhle | John Curtis | John Curtis | Vern Ruhle | Rollie Fingers | 565 | 531 | 34 |
| 1980-09-17 | @ CIN | 145 | L 0-7 | - | | 25,092 | Joe Niekro | Mario Soto | Mario Soto | Joe Niekro | | 565 | 538 | 27 |
| 1980-09-18 | @ CIN | 146 | W 10-2 | - | | 23,861 | Ken Forsch | Frank Pastore | Ken Forsch | Frank Pastore | Joe Sambito | 575 | 540 | 35 |
| 1980-09-19 | @ SFN | 147 | L 3-4 | - | | 4,377 | Joaquin Andujar | Tom Griffin | Tom Griffin | Joaquin Andujar | Al Holland | 578 | 544 | 34 |
| 1980-09-20 | @ SFN | 148 | W 3-2 | - | | 16,770 | Nolan Ryan | Ed Whitson | Dave Smith | Gary Lavelle | Joe Sambito | 581 | 546 | 35 |
| 1980-09-21 | @ SFN | 149 | W 5-1 | - | | 19,844 | Vern Ruhle | Vida Blue | Vern Ruhle | Vida Blue | | 586 | 547 | 39 |
| 1980-09-22 | @ SDN | 150 | W 4-2 | - | | 16,513 | Joe Niekro | Bob Shirley | Joe Niekro | Bob Shirley | | 590 | 549 | 41 |
| 1980-09-23 | @ SDN | 151 | L 4-9 | - | | 4,788 | Randy Niemann | John Curtis | John Curtis | Randy Niemann | | 594 | 558 | 36 |
| 1980-09-24 | @ ATL | 152 | L 2-4 | - | | 24,897 | Joaquin Andujar | Doyle Alexander | Doyle Alexander | Joaquin Andujar | Rick Camp | 596 | 562 | 34 |
| 1980-09-25 | @ ATL | 153 | W 4-2 | - | | 7,926 | Nolan Ryan | Phil Niekro | Nolan Ryan | Phil Niekro | Dave Smith | 600 | 564 | 36 |
| 1980-09-26 | vs CIN | 154 | W 2-0 | - | | 42,486 | Vern Ruhle | Tom Seaver | Vern Ruhle | Tom Seaver | | 602 | 564 | 38 |
| 1980-09-27 | vs CIN | 155 | W 2-0 | - | | 40,305 | Joe Niekro | Mario Soto | Joe Niekro | Mario Soto | Dave Smith | 604 | 564 | 40 |
| 1980-09-28 | vs CIN | 156 | L 5-8 | - | | 32,756 | Ken Forsch | Frank Pastore | Mike LaCoss | Joaquin Andujar | Tom Hume | 609 | 572 | 37 |
| 1980-09-30 | vs ATL | 157 | W 7-3 | - | | 31,973 | Nolan Ryan | Doyle Alexander | Nolan Ryan | Doyle Alexander | Dave Smith | 616 | 575 | 41 |
| 1980-10-01 | vs ATL | 158 | W 5-2 | - | | 35,600 | Vern Ruhle | Phil Niekro | Vern Ruhle | Phil Niekro | | 621 | 577 | 44 |
| 1980-10-02 | vs ATL | 159 | W 3-2 | - | | 45,022 | Joe Niekro | Larry McWilliams | Joe Niekro | Larry McWilliams | Frank LaCorte | 624 | 579 | 45 |
| 1980-10-03 | @ LAN | 160 | L 2-3 | - | | 49,642 | Ken Forsch | Don Sutton | Fernando Valenzuela | Ken Forsch | | 626 | 582 | 44 |
| 1980-10-04 | @ LAN | 161 | L 1-2 | - | | 46,085 | Nolan Ryan | Jerry Reuss | Jerry Reuss | Nolan Ryan | | 627 | 584 | 43 |
| 1980-10-05 | @ LAN | 162 | L 3-4 | - | | 52,339 | Vern Ruhle | Burt Hooton | Steve Howe | Frank LaCorte | Don Sutton | 630 | 588 | 42 |
| 1980-10-06 | @ LAN | 163 | W 7-1 | - | | 51,127 | Joe Niekro | Dave Goltz | Joe Niekro | Dave Goltz | | 637 | 589 | 48 |