| 9/3/2021 | South Dakota | 14 | at | Kansas | 17 | | | MVC (1AA) |
| 9/4/2021 | Texas Tech | 38 | at | Houston | 21 | | | @ AAC |
| Northern Iowa | 10 | at | Iowa State | 16 | | | MVC (1AA) |
| Stanford | 7 | vs | Kansas State | 24 | | Arlington TX | vs P12 |
| West Virginia | 24 | at | Maryland | 30 | | | @ B10 |
| Tulane | 35 | at | Oklahoma | 40 | | | AAC |
| Missouri State | 16 | at | Oklahoma State | 23 | | | MVC (1AA) |
| Duquesne | 3 | at | TCU | 45 | | | NE (1AA) |
| UL Lafayette | 18 | at | Texas | 38 | | | SBC |
| Baylor | 29 | at | Texas State | 20 | | | @ SBC |
| 9/10/2021 | Kansas | 22 | at | Coastal Carolina | 49 | | | @ SBC |
| 9/11/2021 | Texas | 21 | at | Arkansas | 40 | | | @ SEC |
| Texas Southern | 7 | at | Baylor | 66 | | | SWAC (1AA) |
| Iowa | 27 | at | Iowa State | 17 | | | B10 |
| Southern Illinois | 23 | at | Kansas State | 31 | | | MVC (1AA) |
| Western Carolina | 0 | at | Oklahoma | 76 | | | SoCon (1AA) |
| Tulsa | 23 | at | Oklahoma State | 28 | | | AAC |
| California | 32 | at | TCU | 34 | | | P12 |
| Stephen F. Austin | 22 | at | Texas Tech | 28 | | | WAC (1AA) |
| LIU | 0 | at | West Virginia | 66 | | | NE (1AA) |
| 9/18/2021 | Oklahoma State | 21 | at | Boise State | 20 | | | @ MW |
| Baylor | 45 | at | Kansas | 7 | | | |
| Nevada | 17 | at | Kansas State | 38 | | | MW |
| Nebraska | 16 | at | Oklahoma | 23 | | | B10 |
| Rice | 0 | at | Texas | 58 | | | CUSA |
| Florida Intl | 21 | at | Texas Tech | 54 | | | CUSA |
| Iowa State | 48 | at | UNLV | 3 | | | @ MW |
| Virginia Tech | 21 | at | West Virginia | 27 | | | ACC |
| 9/25/2021 | Iowa State | 29 | at | Baylor | 31 | | | |
| Kansas | 33 | at | Duke | 52 | | | @ ACC |
| West Virginia | 13 | at | Oklahoma | 16 | | | |
| Kansas State | 20 | at | Oklahoma State | 31 | | | |
| SMU | 42 | at | TCU | 34 | | | AAC |
| Texas Tech | 35 | at | Texas | 70 | | | |
| 10/2/2021 | Kansas | 7 | at | Iowa State | 59 | | | |
| Oklahoma | 37 | at | Kansas State | 31 | | | |
| Baylor | 14 | at | Oklahoma State | 24 | | | |
| Texas | 32 | at | TCU | 27 | | | |
| Texas Tech | 23 | at | West Virginia | 20 | | | |
| 10/9/2021 | West Virginia | 20 | at | Baylor | 45 | | | |
| Oklahoma | 55 | vs | Texas | 48 | | Dallas TX | |
| TCU | 52 | at | Texas Tech | 31 | | | |
| 10/16/2021 | BYU | 24 | at | Baylor | 38 | | | Ind |
| Texas Tech | 41 | at | Kansas | 14 | | | |
| Iowa State | 33 | at | Kansas State | 20 | | | |
| TCU | 31 | at | Oklahoma | 52 | | | |
| Oklahoma State | 32 | at | Texas | 24 | | | |
| 10/23/2021 | Oklahoma State | 21 | at | Iowa State | 24 | | | |
| Oklahoma | 35 | at | Kansas | 23 | | | |
| West Virginia | 29 | at | TCU | 17 | | | |
| Kansas State | 25 | at | Texas Tech | 24 | | | |
| 10/30/2021 | Texas | 24 | at | Baylor | 31 | | | |
| TCU | 12 | at | Kansas State | 31 | | | |
| Texas Tech | 21 | at | Oklahoma | 52 | | | |
| Kansas | 3 | at | Oklahoma State | 55 | | | |
| Iowa State | 31 | at | West Virginia | 38 | | | |
| 11/6/2021 | Texas | 7 | at | Iowa State | 30 | | | |
| Kansas State | 35 | at | Kansas | 10 | | | |
| Baylor | 28 | at | TCU | 30 | | | |
| Oklahoma State | 24 | at | West Virginia | 3 | | | |
| 11/13/2021 | Oklahoma | 14 | at | Baylor | 27 | | | |
| West Virginia | 17 | at | Kansas State | 34 | | | |
| TCU | 17 | at | Oklahoma State | 63 | | | |
| Kansas | 57 | at | Texas | 56 | OT | | |
| Iowa State | 38 | at | Texas Tech | 41 | | | |
| 11/20/2021 | Baylor | 20 | at | Kansas State | 10 | | | |
| Iowa State | 21 | at | Oklahoma | 28 | | | |
| Kansas | 28 | at | TCU | 31 | | | |
| Oklahoma State | 23 | at | Texas Tech | 0 | | | |
| Texas | 23 | at | West Virginia | 31 | | | |
| 11/26/2021 | TCU | 14 | at | Iowa State | 48 | | | |
| Kansas State | 17 | at | Texas | 22 | | | |
| 11/27/2021 | Texas Tech | 24 | at | Baylor | 27 | | | |
| West Virginia | 34 | at | Kansas | 28 | | | |
| Oklahoma | 33 | at | Oklahoma State | 37 | | | |
| 12/4/2021 | Baylor | 21 | vs | Oklahoma State | 16 | | Big XII Championship - Arlington TX | |
| 12/28/2021 | West Virginia | 6 | vs | Minnesota | 18 | | Guaranteed Rate Bowl - Phoenix AZ | vs B10 |
| Mississippi State | 7 | vs | Texas Tech | 34 | | Liberty Bowl - Memphis TN | vs SEC |
| 12/29/2021 | Clemson | 20 | vs | Iowa State | 13 | | Cheez-It Bowl - Orlando FL | vs ACC |
| Oregon | 32 | vs | Oklahoma | 47 | | Alamo Bowl - San Antonio TX | vs P12 |
| 1/1/2022 | Baylor | 21 | vs | Mississippi | 7 | | Sugar Bowl - New Orleans LA | vs SEC |
| Oklahoma State | 37 | vs | Notre Dame | 35 | | Fiesta Bowl - Glendale AZ | vs ND |
| 1/4/2022 | LSU | 20 | vs | Kansas State | 42 | | Texas Bowl - Houston TX | vs SEC |