| 1980-04-10 | vs SFN | 1 | W 6-4 | 1-0 | 3 | 29,535 | Randy Jones | Bob Knepper | Randy Jones | Bob Knepper | Bob Shirley | 6 | 4 | 2 |
| 1980-04-11 | vs SFN | 2 | W 5-3 | 2-0 | 3 | 20,569 | Rick Wise | Ed Whitson | Rollie Fingers | Gary Lavelle | | 11 | 7 | 4 |
| 1980-04-12 | vs SFN | 3 | W 4-2 | 3-0 | 2 | 22,410 | John Curtis | John Montefusco | John Curtis | John Montefusco | Bob Shirley | 15 | 9 | 6 |
| 1980-04-13 | vs SFN | 4 | L 1-3 | 3-1 | 3 | 16,314 | Eric Rasmussen | Vida Blue | Vida Blue | Eric Rasmussen | Gary Lavelle | 16 | 12 | 4 |
| 1980-04-14 | vs LAN | 5 | W 2-1 | 4-1 | 3 | 28,650 | Randy Jones | Bob Welch | Rollie Fingers | Bobby Castillo | | 18 | 13 | 5 |
| 1980-04-15 | vs LAN | 6 | W 9-5 | 5-1 | 3 | 19,325 | Rick Wise | Rick Sutcliffe | Rick Wise | Rick Sutcliffe | Steve Mura | 27 | 18 | 9 |
| 1980-04-16 | vs LAN | 7 | L 4-10 | 5-2 | 3 | 24,861 | John Curtis | Burt Hooton | Burt Hooton | John Curtis | | 31 | 28 | 3 |
| 1980-04-17 | @ SFN | 8 | L 3-7 | 5-3 | 3 | 51,123 | Eric Rasmussen | Vida Blue | Vida Blue | Eric Rasmussen | | 34 | 35 | -1 |
| 1980-04-18 | @ SFN | 9 | L 2-5 | 5-4 | 3 | 12,241 | Randy Jones | Bob Knepper | Bob Knepper | Randy Jones | | 36 | 40 | -4 |
| 1980-04-19 | @ SFN | 10 | W 3-0 | 6-4 | 3 | 11,024 | Gary Lucas | Ed Whitson | Gary Lucas | Ed Whitson | Rollie Fingers | 39 | 40 | -1 |
| 1980-04-20 | @ SFN | 11 | L 1-5 | 6-5 | 3 | 26,048 | Rick Wise | John Montefusco | John Montefusco | Rick Wise | | 40 | 45 | -5 |
| 1980-04-22 | @ ATL | 12 | L 2-3 | 6-6 | 3 | 4,710 | John Curtis | Phil Niekro | Al Hrabosky | Bob Shirley | | 42 | 48 | -6 |
| 1980-04-23 | @ ATL | 13 | L 1-2 | 6-7 | 4 | 4,166 | Randy Jones | Rick Matula | Rick Matula | Randy Jones | Al Hrabosky | 43 | 50 | -7 |
| 1980-04-24 | @ ATL | 14 | L 7-8 | 6-8 | 4 | 4,498 | Eric Rasmussen | Doyle Alexander | Gene Garber | Rollie Fingers | | 50 | 58 | -8 |
| 1980-04-25 | @ LAN | 15 | L 3-6 | 6-9 | 4 | 39,720 | Rick Wise | Rick Sutcliffe | Bobby Castillo | Dennis Kinney | Steve Howe | 53 | 64 | -11 |
| 1980-04-26 | @ LAN | 16 | L 3-4 | 6-10 | 4 | 48,568 | Gary Lucas | Burt Hooton | Joe Beckwith | Rollie Fingers | | 56 | 68 | -12 |
| 1980-04-27 | @ LAN | 17 | L 1-3 | 6-11 | 5 | 42,756 | John Curtis | Don Sutton | Don Sutton | John Curtis | Charlie Hough | 57 | 71 | -14 |
| 1980-04-30 | vs ATL | 18 | W 2-1 | 7-11 | 4 | 9,018 | Eric Rasmussen | Rick Matula | Eric Rasmussen | Rick Matula | Bob Shirley | 59 | 72 | -13 |
| 1980-05-01 | vs ATL | 19 | W 4-3 | 8-11 | 4 | 12,131 | Randy Jones | Doyle Alexander | Bob Shirley | Rick Camp | | 63 | 75 | -12 |
| 1980-05-02 | @ NYN | 20 | W 1-0 | 9-11 | 4 | 8,037 | Rick Wise | Ray Burris | Rick Wise | Ray Burris | Steve Mura | 64 | 75 | -11 |
| 1980-05-03 | @ NYN | 21 | W 2-1 | 10-11 | 4 | 9,462 | Gary Lucas | Craig Swan | Gary Lucas | Craig Swan | Rollie Fingers | 66 | 76 | -10 |
| 1980-05-04 | @ NYN | 22 | W 4-3 | 11-12 | 4 | 0 | John Curtis | Kevin Kobel | John Curtis | Jeff Reardon | Bob Shirley | 70 | 79 | -9 |
| 1980-05-04 | @ NYN | 23 | L 2-6 | 11-12 | 4 | 26,980 | Eric Rasmussen | John Pacella | Ed Glynn | Eric Rasmussen | Neil Allen | 72 | 85 | -13 |
| 1980-05-06 | @ CHN | 24 | W 4-0 | 12-12 | 4 | 9,908 | Randy Jones | Guillermo Hernandez | Randy Jones | Guillermo Hernandez | | 76 | 85 | -9 |
| 1980-05-07 | @ CHN | 25 | L 4-7 | 12-13 | 4 | 7,401 | Rick Wise | Mike Krukow | Mike Krukow | Rick Wise | Bruce Sutter | 80 | 92 | -12 |
| 1980-05-08 | @ CHN | 26 | W 9-6 | 13-13 | 4 | 6,692 | Gary Lucas | Rick Reuschel | Bob Shirley | Bruce Sutter | Rollie Fingers | 89 | 98 | -9 |
| 1980-05-09 | vs PIT | 27 | L 3-4 | 13-14 | 4 | 34,078 | John Curtis | Jim Bibby | Kent Tekulve | Rollie Fingers | | 92 | 102 | -10 |
| 1980-05-10 | vs PIT | 28 | L 5-9 | 13-15 | 4 | 18,168 | Eric Rasmussen | Don Robinson | Don Robinson | Eric Rasmussen | Enrique Romo | 97 | 111 | -14 |
| 1980-05-11 | vs PIT | 29 | W 5-0 | 14-15 | 4 | 22,522 | Randy Jones | John Candelaria | Randy Jones | John Candelaria | | 102 | 111 | -9 |
| 1980-05-13 | vs SLN | 30 | W 3-2 | 15-15 | 4 | 9,958 | Rick Wise | Don Hood | Rollie Fingers | Jim Kaat | | 105 | 113 | -8 |
| 1980-05-14 | vs SLN | 31 | L 1-2 | 15-16 | 4 | 11,131 | Gary Lucas | Roy Thomas | Roy Thomas | Gary Lucas | Mark Littell | 106 | 115 | -9 |
| 1980-05-15 | vs SLN | 32 | W 2-1 | 16-16 | 4 | 10,265 | John Curtis | Pete Vuckovich | John Curtis | Pete Vuckovich | Rollie Fingers | 108 | 116 | -8 |
| 1980-05-16 | vs CHN | 33 | W 3-0 | 17-16 | 4 | 19,028 | Randy Jones | Mike Krukow | Randy Jones | Mike Krukow | | 111 | 116 | -5 |
| 1980-05-17 | vs CHN | 34 | L 1-2 | 17-17 | 4 | 26,587 | Eric Rasmussen | Rick Reuschel | Rick Reuschel | Eric Rasmussen | Bruce Sutter | 112 | 118 | -6 |
| 1980-05-18 | vs CHN | 35 | W 4-3 | 18-17 | 4 | 16,303 | Rick Wise | Dennis Lamp | Rollie Fingers | Bruce Sutter | | 116 | 121 | -5 |
| 1980-05-21 | @ PIT | 36 | L 3-4 | 18-19 | 4 | 0 | Randy Jones | John Candelaria | Enrique Romo | Rollie Fingers | | 119 | 125 | -6 |
| 1980-05-21 | @ PIT | 37 | L 2-3 | 18-19 | 4 | 17,301 | John Curtis | Don Robinson | Grant Jackson | John Curtis | Kent Tekulve | 121 | 128 | -7 |
| 1980-05-22 | @ PIT | 38 | W 6-4 | 19-19 | 4 | 12,496 | Gary Lucas | Bert Blyleven | Bob Shirley | Kent Tekulve | Rollie Fingers | 127 | 132 | -5 |
| 1980-05-23 | @ SLN | 39 | W 2-0 | 20-19 | 4 | 7,245 | Rick Wise | John Fulgham | Bob Shirley | Jim Kaat | | 129 | 132 | -3 |
| 1980-05-24 | @ SLN | 40 | W 8-4 | 21-19 | 4 | 14,990 | Eric Rasmussen | Silvio Martinez | Dennis Kinney | Donnie Moore | | 137 | 136 | 1 |
| 1980-05-25 | @ SLN | 41 | W 11-5 | 22-19 | 4 | 14,157 | Randy Jones | Pete Vuckovich | Rollie Fingers | Roy Thomas | John D'Acquisto | 148 | 141 | 7 |
| 1980-05-26 | @ HOU | 42 | L 1-4 | 22-20 | 4 | 18,242 | John Curtis | J.R. Richard | J.R. Richard | John Curtis | Joe Sambito | 149 | 145 | 4 |
| 1980-05-27 | @ HOU | 43 | L 3-4 | 22-21 | 4 | 18,246 | Gary Lucas | Joe Niekro | Frank LaCorte | Rollie Fingers | | 152 | 149 | 3 |
| 1980-05-28 | @ HOU | 44 | L 0-1 | 22-22 | 4 | 19,697 | Rick Wise | Nolan Ryan | Nolan Ryan | Rick Wise | | 152 | 150 | 2 |
| 1980-05-29 | vs CIN | 45 | L 3-5 | 22-23 | 4 | 11,677 | Randy Jones | Frank Pastore | Frank Pastore | Randy Jones | Tom Hume | 155 | 155 | 0 |
| 1980-05-30 | vs CIN | 46 | L 3-5 | 22-24 | 4 | 26,777 | Steve Mura | Charlie Leibrandt | Charlie Leibrandt | Steve Mura | Doug Bair | 158 | 160 | -2 |
| 1980-05-31 | vs CIN | 47 | W 7-5 | 23-24 | 4 | 29,316 | John Curtis | Paul Moskau | Bob Shirley | Tom Hume | Rollie Fingers | 165 | 165 | 0 |
| 1980-06-01 | vs CIN | 48 | L 6-7 | 23-25 | 4 | 21,044 | Gary Lucas | Mario Soto | Sheldon Burnside | Gary Lucas | Tom Hume | 171 | 172 | -1 |
| 1980-06-02 | vs HOU | 49 | W 3-0 | 24-25 | 4 | 27,176 | Rick Wise | Nolan Ryan | Rick Wise | Nolan Ryan | Eric Rasmussen | 174 | 172 | 2 |
| 1980-06-03 | vs HOU | 50 | L 2-3 | 24-26 | 4 | 12,363 | Randy Jones | Vern Ruhle | Vern Ruhle | Randy Jones | Frank LaCorte | 176 | 175 | 1 |
| 1980-06-04 | vs HOU | 51 | L 3-4 | 24-27 | 4 | 13,619 | Steve Mura | Ken Forsch | Ken Forsch | Rollie Fingers | Joe Sambito | 179 | 179 | 0 |
| 1980-06-06 | @ CIN | 52 | L 2-4 | 24-28 | 4 | 23,329 | John Curtis | Frank Pastore | Frank Pastore | John D'Acquisto | Tom Hume | 181 | 183 | -2 |
| 1980-06-07 | @ CIN | 53 | W 6-1 | 25-28 | 4 | 27,004 | Gary Lucas | Mike LaCoss | Gary Lucas | Mike LaCoss | Rollie Fingers | 187 | 184 | 3 |
| 1980-06-08 | @ CIN | 54 | L 0-1 | 25-29 | 4 | 26,272 | Randy Jones | Charlie Leibrandt | Charlie Leibrandt | Randy Jones | | 187 | 185 | 2 |
| 1980-06-09 | @ CIN | 55 | L 6-6 | 25-30 | 4 | 19,688 | Steve Mura | Paul Moskau | | | | 193 | 191 | 2 |
| 1980-06-10 | @ MON | 56 | L 4-8 | 25-31 | 4 | 17,439 | Rick Wise | Scott Sanderson | Stan Bahnsen | Eric Rasmussen | Elias Sosa | 197 | 199 | -2 |
| 1980-06-11 | @ MON | 57 | L 6-7 | 25-32 | 4 | 13,948 | John Curtis | Bill Gullickson | Elias Sosa | Bob Shirley | | 203 | 206 | -3 |
| 1980-06-12 | @ MON | 58 | L 1-9 | 25-33 | 4 | 20,724 | Gary Lucas | Charlie Lea | Charlie Lea | Gary Lucas | | 204 | 215 | -11 |
| 1980-06-13 | @ PHI | 59 | L 6-9 | 25-34 | 5 | 37,873 | Randy Jones | Dick Ruthven | Dick Ruthven | Randy Jones | | 210 | 224 | -14 |
| 1980-06-14 | @ PHI | 60 | L 1-3 | 25-35 | 5 | 35,231 | Steve Mura | Steve Carlton | Steve Carlton | Steve Mura | Tug McGraw | 211 | 227 | -16 |
| 1980-06-15 | @ PHI | 61 | L 5-8 | 25-36 | 6 | 36,374 | Rick Wise | Bob Walk | Bob Walk | Rick Wise | Lerrin LaGrow | 216 | 235 | -19 |
| 1980-06-16 | vs NYN | 62 | W 3-2 | 26-36 | 6 | 8,395 | John Curtis | Craig Swan | Rollie Fingers | Jeff Reardon | Bob Shirley | 219 | 237 | -18 |
| 1980-06-17 | vs NYN | 63 | W 2-1 | 27-36 | 4 | 11,448 | Gary Lucas | John Pacella | Rollie Fingers | Tom Hausman | | 221 | 238 | -17 |
| 1980-06-18 | vs PHI | 64 | L 1-5 | 27-37 | 6 | 15,621 | Eric Rasmussen | Steve Carlton | Steve Carlton | Bob Shirley | | 222 | 243 | -21 |
| 1980-06-19 | vs PHI | 65 | W 4-3 | 28-37 | 6 | 16,712 | Juan Eichelberger | Bob Walk | Dennis Kinney | Kevin Saucier | Rollie Fingers | 226 | 246 | -20 |
| 1980-06-20 | vs MON | 66 | W 4-2 | 29-37 | 5 | 14,266 | Steve Mura | Scott Sanderson | Steve Mura | Scott Sanderson | Bob Shirley | 230 | 248 | -18 |
| 1980-06-21 | vs MON | 67 | L 4-7 | 29-38 | 6 | 13,726 | John Curtis | Charlie Lea | Charlie Lea | John Curtis | Elias Sosa | 234 | 255 | -21 |
| 1980-06-22 | vs MON | 68 | L 0-2 | 29-39 | 6 | 14,388 | Gary Lucas | Steve Rogers | Steve Rogers | Gary Lucas | | 234 | 257 | -23 |
| 1980-06-24 | vs SFN | 69 | W 5-3 | 30-39 | 5 | 10,772 | Eric Rasmussen | Bob Knepper | John D'Acquisto | Bob Knepper | | 239 | 260 | -21 |
| 1980-06-25 | vs SFN | 70 | W 7-3 | 31-39 | 4 | 11,336 | Juan Eichelberger | Allen Ripley | Juan Eichelberger | Allen Ripley | Rollie Fingers | 246 | 263 | -17 |
| 1980-06-26 | vs SFN | 71 | L 1-2 | 31-40 | 5 | 11,321 | Steve Mura | Ed Whitson | Ed Whitson | Steve Mura | Greg Minton | 247 | 265 | -18 |
| 1980-06-27 | vs ATL | 72 | L 3-5 | 31-41 | 6 | 15,303 | John Curtis | Doyle Alexander | Rick Camp | John Curtis | Gene Garber | 250 | 270 | -20 |
| 1980-06-28 | vs ATL | 73 | L 4-5 | 32-42 | 6 | 0 | Gary Lucas | Tommy Boggs | Larry Bradford | Bob Shirley | Gene Garber | 254 | 275 | -21 |
| 1980-06-28 | vs ATL | 74 | W 3-2 | 32-42 | 6 | 17,554 | Dennis Blair | Phil Niekro | John D'Acquisto | Rick Camp | | 257 | 277 | -20 |
| 1980-06-29 | vs ATL | 75 | L 2-4 | 32-43 | 6 | 11,938 | Eric Rasmussen | Larry McWilliams | Larry McWilliams | Eric Rasmussen | | 259 | 281 | -22 |
| 1980-06-30 | @ LAN | 76 | W 4-3 | 33-43 | 6 | 29,756 | Juan Eichelberger | Bob Welch | Juan Eichelberger | Bob Welch | Bob Shirley | 263 | 284 | -21 |
| 1980-07-01 | @ LAN | 77 | W 4-1 | 34-43 | 6 | 38,801 | Steve Mura | Jerry Reuss | Steve Mura | Jerry Reuss | Rollie Fingers | 267 | 285 | -18 |
| 1980-07-02 | @ LAN | 78 | L 7-10 | 34-44 | 6 | 33,232 | John Curtis | Dave Goltz | Rick Sutcliffe | Dennis Blair | | 274 | 295 | -21 |
| 1980-07-03 | @ LAN | 79 | L 4-5 | 34-45 | 6 | 31,375 | Gary Lucas | Burt Hooton | Bobby Castillo | Bob Shirley | | 278 | 300 | -22 |
| 1980-07-04 | @ ATL | 80 | L 0-9 | 34-46 | 6 | 46,071 | Eric Rasmussen | Larry McWilliams | Larry McWilliams | Eric Rasmussen | | 278 | 309 | -31 |
| 1980-07-05 | @ ATL | 81 | L 2-3 | 34-47 | 6 | 18,932 | Juan Eichelberger | Rick Matula | Rick Matula | Rollie Fingers | | 280 | 312 | -32 |
| 1980-07-06 | @ ATL | 82 | L 5-6 | 34-48 | 6 | 14,302 | Steve Mura | Doyle Alexander | Doyle Alexander | Bob Shirley | Phil Niekro | 285 | 318 | -33 |
| 1980-07-10 | @ SFN | 83 | L 2-9 | 34-49 | 6 | 8,175 | Randy Jones | Bob Knepper | Bob Knepper | Randy Jones | | 287 | 327 | -40 |
| 1980-07-11 | @ SFN | 84 | L 3-7 | 34-50 | 6 | 7,782 | John Curtis | Ed Whitson | Ed Whitson | John Curtis | | 290 | 334 | -44 |
| 1980-07-12 | vs LAN | 85 | W 3-2 | 35-50 | 6 | 39,605 | Rick Wise | Don Sutton | Eric Rasmussen | Joe Beckwith | | 293 | 336 | -43 |
| 1980-07-13 | vs LAN | 86 | W 4-3 | 36-50 | 6 | 18,232 | Juan Eichelberger | Bob Welch | Dennis Kinney | Joe Beckwith | | 297 | 339 | -42 |
| 1980-07-14 | vs LAN | 87 | W 6-3 | 37-50 | 6 | 22,370 | Steve Mura | Rick Sutcliffe | Steve Mura | Rick Sutcliffe | | 303 | 342 | -39 |
| 1980-07-15 | @ SLN | 88 | L 3-5 | 37-51 | 6 | 13,519 | Randy Jones | Bob Forsch | Bob Forsch | Randy Jones | John Littlefield | 306 | 347 | -41 |
| 1980-07-16 | @ SLN | 89 | L 0-3 | 37-52 | 6 | 12,343 | Gary Lucas | Pete Vuckovich | Pete Vuckovich | Gary Lucas | | 306 | 350 | -44 |
| 1980-07-17 | @ SLN | 90 | L 3-15 | 37-53 | 6 | 12,156 | Rick Wise | Jim Kaat | Jim Kaat | Rick Wise | | 309 | 365 | -56 |
| 1980-07-18 | @ CHN | 91 | W 2-1 | 38-53 | 6 | 14,007 | Bob Shirley | Doug Capilla | Bob Shirley | Doug Capilla | Rollie Fingers | 311 | 366 | -55 |
| 1980-07-19 | @ CHN | 92 | L 7-8 | 38-54 | 6 | 24,369 | Steve Mura | Mike Krukow | Bill Caudill | Dennis Kinney | | 318 | 374 | -56 |
| 1980-07-20 | @ CHN | 93 | L 0-6 | 38-55 | 6 | 23,325 | Randy Jones | Lynn McGlothen | Lynn McGlothen | Randy Jones | | 318 | 380 | -62 |
| 1980-07-22 | vs PIT | 94 | L 3-4 | 38-56 | 6 | 17,504 | Gary Lucas | Jim Bibby | Jim Bibby | Gary Lucas | Kent Tekulve | 321 | 384 | -63 |
| 1980-07-23 | vs PIT | 95 | W 3-2 | 39-56 | 6 | 14,608 | Rick Wise | Rick Rhoden | Rollie Fingers | Enrique Romo | | 324 | 386 | -62 |
| 1980-07-24 | vs PIT | 96 | L 1-7 | 39-57 | 6 | 15,746 | Bob Shirley | Bert Blyleven | Bert Blyleven | Bob Shirley | | 325 | 393 | -68 |
| 1980-07-25 | vs SLN | 97 | L 2-3 | 39-58 | 6 | 12,815 | Randy Jones | Bob Sykes | Bob Sykes | Dennis Kinney | John Littlefield | 327 | 396 | -69 |
| 1980-07-26 | vs SLN | 98 | W 4-3 | 40-58 | 6 | 15,310 | Steve Mura | Bob Forsch | Dennis Kinney | Don Hood | | 331 | 399 | -68 |
| 1980-07-27 | vs SLN | 99 | W 5-2 | 41-58 | 6 | 11,381 | Gary Lucas | Pete Vuckovich | Gary Lucas | Pete Vuckovich | Rollie Fingers | 336 | 401 | -65 |
| 1980-07-28 | vs CHN | 100 | W 4-2 | 42-58 | 6 | 15,775 | John Curtis | Dennis Lamp | Rollie Fingers | George Riley | | 340 | 403 | -63 |
| 1980-07-29 | vs CHN | 101 | W 3-1 | 43-58 | 6 | 11,802 | Randy Jones | Doug Capilla | Randy Jones | Doug Capilla | | 343 | 404 | -61 |
| 1980-07-30 | vs CHN | 102 | W 5-2 | 44-58 | 6 | 12,036 | Rick Wise | Lynn McGlothen | Bob Shirley | Bruce Sutter | | 348 | 406 | -58 |
| 1980-08-01 | @ PIT | 103 | W 1-0 | 45-58 | 6 | 22,304 | Steve Mura | Jim Bibby | Steve Mura | Jim Bibby | Rollie Fingers | 349 | 406 | -57 |
| 1980-08-03 | @ PIT | 104 | W 5-2 | 47-58 | 5 | 0 | John Curtis | Rick Rhoden | John Curtis | Rick Rhoden | | 354 | 408 | -54 |
| 1980-08-03 | @ PIT | 105 | W 4-1 | 47-58 | 5 | 20,517 | Bob Shirley | Don Robinson | Bob Shirley | Don Robinson | Rollie Fingers | 358 | 409 | -51 |
| 1980-08-04 | @ CIN | 106 | L 1-7 | 47-60 | 6 | 0 | Randy Jones | Tom Seaver | Tom Seaver | Randy Jones | Tom Hume | 359 | 416 | -57 |
| 1980-08-04 | @ CIN | 107 | L 2-11 | 47-60 | 6 | 25,162 | Rick Wise | Joe Price | Mario Soto | Dennis Kinney | | 361 | 427 | -66 |
| 1980-08-05 | @ CIN | 108 | L 2-9 | 47-61 | 6 | 23,180 | Gary Lucas | Paul Moskau | Paul Moskau | Gary Lucas | | 363 | 436 | -73 |
| 1980-08-06 | @ CIN | 109 | L 3-4 | 47-62 | 6 | 27,070 | Steve Mura | Charlie Leibrandt | Tom Hume | John D'Acquisto | | 366 | 440 | -74 |
| 1980-08-07 | @ HOU | 110 | W 5-1 | 48-62 | 6 | 20,044 | Bob Shirley | Joe Niekro | Bob Shirley | Joe Niekro | | 371 | 441 | -70 |
| 1980-08-08 | @ HOU | 111 | W 5-3 | 49-62 | 6 | 15,207 | Randy Jones | Vern Ruhle | Juan Eichelberger | Joe Sambito | Rollie Fingers | 376 | 444 | -68 |
| 1980-08-09 | @ HOU | 112 | L 5-9 | 49-63 | 6 | 21,233 | John Curtis | Nolan Ryan | Dave Smith | John D'Acquisto | | 381 | 453 | -72 |
| 1980-08-10 | @ HOU | 113 | W 3-2 | 50-63 | 6 | 20,514 | Rick Wise | Joaquin Andujar | Rick Wise | Joe Sambito | | 384 | 455 | -71 |
| 1980-08-11 | vs CIN | 114 | L 0-1 | 50-64 | 6 | 16,346 | Steve Mura | Charlie Leibrandt | Charlie Leibrandt | Steve Mura | Tom Hume | 384 | 456 | -72 |
| 1980-08-12 | vs CIN | 115 | L 2-3 | 50-65 | 6 | 15,579 | Randy Jones | Joe Price | Joe Price | Randy Jones | | 386 | 459 | -73 |
| 1980-08-13 | vs CIN | 116 | L 3-4 | 50-66 | 6 | 13,141 | Bob Shirley | Mike LaCoss | Mario Soto | Bob Shirley | | 389 | 463 | -74 |
| 1980-08-14 | vs HOU | 117 | L 1-2 | 50-67 | 6 | 12,150 | John Curtis | Nolan Ryan | Nolan Ryan | John Curtis | | 390 | 465 | -75 |
| 1980-08-15 | vs HOU | 118 | L 1-3 | 50-68 | 6 | 14,177 | Rick Wise | Gordie Pladson | Dave Smith | Eric Rasmussen | | 391 | 468 | -77 |
| 1980-08-17 | vs HOU | 119 | L 0-5 | 50-70 | 6 | 0 | Randy Jones | Ken Forsch | Ken Forsch | Randy Jones | | 391 | 473 | -82 |
| 1980-08-17 | vs HOU | 120 | L 2-9 | 50-70 | 6 | 16,120 | Steve Mura | Joe Niekro | Joe Niekro | Steve Mura | | 393 | 482 | -89 |
| 1980-08-19 | @ PHI | 121 | L 4-7 | 50-71 | 6 | 30,588 | Bob Shirley | Dick Ruthven | Dick Ruthven | Bob Shirley | Tug McGraw | 397 | 489 | -92 |
| 1980-08-20 | @ PHI | 122 | W 7-5 | 51-71 | 6 | 30,403 | Juan Eichelberger | Nino Espinosa | John Curtis | Nino Espinosa | Rollie Fingers | 404 | 494 | -90 |
| 1980-08-21 | @ PHI | 123 | L 8-9 | 51-72 | 6 | 36,201 | Rick Wise | Bob Walk | Kevin Saucier | Dennis Kinney | | 412 | 503 | -91 |
| 1980-08-22 | @ MON | 124 | L 2-6 | 51-73 | 6 | 26,443 | Randy Jones | Fred Norman | Fred Norman | Randy Jones | | 414 | 509 | -95 |
| 1980-08-23 | @ MON | 125 | L 0-2 | 51-74 | 6 | 41,354 | Steve Mura | Bill Gullickson | Bill Gullickson | Steve Mura | John D'Acquisto | 414 | 511 | -97 |
| 1980-08-24 | @ MON | 126 | L 9-12 | 51-75 | 6 | 37,650 | Bob Shirley | Charlie Lea | Elias Sosa | Rollie Fingers | John D'Acquisto | 423 | 523 | -100 |
| 1980-08-26 | @ NYN | 127 | W 8-6 | 52-75 | 6 | 9,844 | Juan Eichelberger | Mark Bomback | Eric Rasmussen | Pete Falcone | Dennis Kinney | 431 | 529 | -98 |
| 1980-08-27 | @ NYN | 128 | W 4-1 | 53-75 | 6 | 16,612 | Rick Wise | Ray Burris | Rick Wise | Ray Burris | Rollie Fingers | 435 | 530 | -95 |
| 1980-08-29 | vs PHI | 129 | L 2-3 | 53-76 | 6 | 10,742 | Steve Mura | Larry Christenson | Larry Christenson | Steve Mura | Tug McGraw | 437 | 533 | -96 |
| 1980-08-30 | vs PHI | 130 | L 1-6 | 54-77 | 6 | 0 | Bob Shirley | Dick Ruthven | Dick Ruthven | Bob Shirley | | 438 | 539 | -101 |
| 1980-08-30 | vs PHI | 131 | W 5-1 | 54-77 | 6 | 13,209 | John Curtis | Nino Espinosa | John Curtis | Nino Espinosa | | 443 | 540 | -97 |
| 1980-08-31 | vs PHI | 132 | W 10-3 | 55-77 | 6 | 7,815 | Juan Eichelberger | Bob Walk | Gary Lucas | Bob Walk | Rollie Fingers | 453 | 543 | -90 |
| 1980-09-01 | vs MON | 133 | L 3-5 | 55-78 | 6 | 9,385 | Rick Wise | Scott Sanderson | Scott Sanderson | Rick Wise | Woodie Fryman | 456 | 548 | -92 |
| 1980-09-02 | vs MON | 134 | L 1-2 | 55-79 | 6 | 6,082 | Eric Rasmussen | Charlie Lea | Charlie Lea | Eric Rasmussen | Woodie Fryman | 457 | 550 | -93 |
| 1980-09-03 | vs MON | 135 | W 4-3 | 56-79 | 6 | 6,685 | Steve Mura | Fred Norman | Steve Mura | Fred Norman | Rollie Fingers | 461 | 553 | -92 |
| 1980-09-04 | vs NYN | 136 | W 3-2 | 57-79 | 6 | 2,635 | John Curtis | Mike Scott | John Curtis | Neil Allen | | 464 | 555 | -91 |
| 1980-09-05 | vs NYN | 137 | W 4-2 | 58-79 | 6 | 7,137 | Juan Eichelberger | Mark Bomback | Juan Eichelberger | Mark Bomback | Gary Lucas | 468 | 557 | -89 |
| 1980-09-06 | vs NYN | 138 | W 8-7 | 59-79 | 6 | 7,877 | Rick Wise | Ray Burris | Rick Wise | Ray Burris | Rollie Fingers | 476 | 564 | -88 |
| 1980-09-07 | vs NYN | 139 | W 5-2 | 60-79 | 6 | 5,141 | Bob Shirley | John Pacella | Bob Shirley | John Pacella | Gary Lucas | 481 | 566 | -85 |
| 1980-09-09 | vs SFN | 140 | W 12-5 | 61-79 | 6 | 6,241 | Steve Mura | Allen Ripley | Steve Mura | Allen Ripley | | 493 | 571 | -78 |
| 1980-09-10 | vs SFN | 141 | W 4-2 | 62-79 | 6 | 6,834 | John Curtis | Bob Knepper | Rollie Fingers | Greg Minton | Gary Lucas | 497 | 573 | -76 |
| 1980-09-12 | @ ATL | 142 | L 2-6 | 62-80 | 6 | 8,881 | Juan Eichelberger | Phil Niekro | Phil Niekro | Juan Eichelberger | Rick Camp | 499 | 579 | -80 |
| 1980-09-13 | @ ATL | 143 | L 3-5 | 62-81 | 6 | 12,990 | Rick Wise | Rick Matula | Rick Matula | Rick Wise | Rick Camp | 502 | 584 | -82 |
| 1980-09-14 | @ ATL | 144 | L 3-4 | 62-82 | 6 | 9,270 | Steve Mura | Doyle Alexander | Rick Camp | Gary Lucas | | 505 | 588 | -83 |
| 1980-09-15 | @ HOU | 145 | W 6-3 | 63-82 | 6 | 9,578 | Bob Shirley | Nolan Ryan | Bob Shirley | Nolan Ryan | | 511 | 591 | -80 |
| 1980-09-16 | @ HOU | 146 | W 4-3 | 64-82 | 6 | 20,383 | John Curtis | Vern Ruhle | John Curtis | Vern Ruhle | Rollie Fingers | 515 | 594 | -79 |
| 1980-09-17 | @ LAN | 147 | L 1-2 | 64-83 | 6 | 28,822 | Juan Eichelberger | Don Sutton | Don Sutton | Juan Eichelberger | Steve Howe | 516 | 596 | -80 |
| 1980-09-18 | @ LAN | 148 | L 3-7 | 64-84 | 6 | 30,738 | Rick Wise | Bob Welch | Bob Welch | Rick Wise | Bobby Castillo | 519 | 603 | -84 |
| 1980-09-19 | vs ATL | 149 | W 7-4 | 65-84 | 6 | 5,893 | Steve Mura | Doyle Alexander | Steve Mura | Doyle Alexander | Rollie Fingers | 526 | 607 | -81 |
| 1980-09-20 | vs ATL | 150 | W 3-2 | 66-84 | 6 | 7,180 | George Stablein | Tommy Boggs | Eric Rasmussen | Al Hrabosky | | 529 | 609 | -80 |
| 1980-09-21 | vs ATL | 151 | W 3-1 | 67-84 | 6 | 2,846 | Tom Tellmann | Phil Niekro | Tom Tellmann | Phil Niekro | | 532 | 610 | -78 |
| 1980-09-22 | vs HOU | 152 | L 2-4 | 67-85 | 6 | 16,513 | Bob Shirley | Joe Niekro | Joe Niekro | Bob Shirley | | 534 | 614 | -80 |
| 1980-09-23 | vs HOU | 153 | W 9-4 | 68-85 | 6 | 4,788 | John Curtis | Randy Niemann | John Curtis | Randy Niemann | | 543 | 618 | -75 |
| 1980-09-24 | vs CIN | 154 | L 6-7 | 68-86 | 6 | 7,757 | Juan Eichelberger | Joe Price | Doug Bair | Rollie Fingers | | 549 | 625 | -76 |
| 1980-09-25 | vs CIN | 155 | L 3-5 | 68-87 | 6 | 5,309 | Rick Wise | Charlie Leibrandt | Doug Bair | Dennis Kinney | | 552 | 630 | -78 |
| 1980-09-26 | vs LAN | 156 | W 3-2 | 69-87 | 6 | 14,836 | Steve Mura | Dave Goltz | Tom Tellmann | Dave Goltz | Rollie Fingers | 555 | 632 | -77 |
| 1980-09-27 | vs LAN | 157 | L 4-6 | 69-88 | 6 | 19,260 | Eric Rasmussen | Don Sutton | Don Sutton | Eric Rasmussen | Fernando Valenzuela | 559 | 638 | -79 |
| 1980-09-28 | vs LAN | 158 | W 7-5 | 70-88 | 6 | 17,971 | Juan Eichelberger | Bob Welch | Rollie Fingers | Steve Howe | Tom Tellmann | 566 | 643 | -77 |
| 1980-09-30 | @ CIN | 159 | W 3-2 | 71-88 | 6 | 14,779 | John Curtis | Charlie Leibrandt | John Curtis | Charlie Leibrandt | | 569 | 645 | -76 |
| 1980-10-01 | @ CIN | 160 | L 1-2 | 71-89 | 6 | 11,764 | Bob Shirley | Tom Seaver | Tom Hume | Bob Shirley | | 570 | 647 | -77 |
| 1980-10-03 | @ SFN | 161 | W 12-0 | 72-89 | 6 | 2,740 | Steve Mura | Allen Ripley | Steve Mura | Allen Ripley | | 582 | 647 | -65 |
| 1980-10-04 | @ SFN | 162 | L 2-4 | 72-90 | 6 | 3,194 | George Stablein | Tom Griffin | Tom Griffin | George Stablein | Greg Minton | 584 | 651 | -67 |
| 1980-10-05 | @ SFN | 163 | W 7-3 | 73-90 | 6 | 14,680 | Tom Tellmann | Ed Whitson | Tom Tellmann | Ed Whitson | | 591 | 654 | -63 |