Schedule:
| Game | Date | Away Team (Rank) | Away Score | Home Team (Rank) | Home Score | Game Status | Result | Margin |
|---|---|---|---|---|---|---|---|---|
| 1 | 2021-09-04 | Northern Iowa | 10 | Iowa State | 16 | Final | W | 6 |
| 2 | 2021-09-11 | Iowa | 27 | Iowa State | 17 | Final | L | -10 |
| 3 | 2021-09-18 | Iowa State | 48 | UNLV | 3 | Final | W | 45 |
| 4 | 2021-09-25 | Iowa State | 29 | Baylor | 31 | Final | L | -2 |
| 5 | 2021-10-02 | Kansas | 7 | Iowa State | 59 | Final | W | 52 |
| 6 | 2021-10-16 | Iowa State | 33 | Kansas State | 20 | Final | W | 13 |
| 7 | 2021-10-23 | Oklahoma State | 21 | Iowa State | 24 | Final | W | 3 |
| 8 | 2021-10-30 | Iowa State | 31 | West Virginia | 38 | Final | L | -7 |
| 9 | 2021-11-06 | Texas | 7 | Iowa State | 30 | Final | W | 23 |
| 10 | 2021-11-13 | Iowa State | 38 | Texas Tech | 41 | Final | L | -3 |
| 11 | 2021-11-20 | Iowa State | 21 | Oklahoma | 28 | Final | L | -7 |
| 12 | 2021-11-26 | TCU (81) | 14 | Iowa State (35) | 48 | Final | W | 34 |
| 13 | 2021-12-29 | Clemson (13) | 20 | Iowa State (34) | 13 | Final | L | -7 |