| 9/4/2021 | Northern Iowa (6-6) | 10 | at | Iowa State | 16 | MVC (1AA) | ||
| 9/11/2021 | Iowa (10-4) | 27 | at | Iowa State | 17 | B10 | ||
| 9/18/2021 | Iowa State | 48 | at | UNLV (2-10) | 3 | at MW | ||
| 9/25/2021 | Iowa State | 29 | at | Baylor (12-2,8-2) | 31 | |||
| 10/2/2021 | Kansas (2-10,1-8) | 7 | at | Iowa State | 59 | |||
| 10/16/2021 | Iowa State | 33 | at | Kansas State (8-5,4-5) | 20 | |||
| 10/23/2021 | Oklahoma State (12-2,8-2) | 21 | at | Iowa State | 24 | |||
| 10/30/2021 | Iowa State | 31 | at | West Virginia (6-7,4-5) | 38 | |||
| 11/6/2021 | Texas (5-7,3-6) | 7 | at | Iowa State | 30 | |||
| 11/13/2021 | Iowa State | 38 | at | Texas Tech (7-6,3-6) | 41 | |||
| 11/20/2021 | Iowa State | 21 | at | Oklahoma (11-2,7-2) | 28 | |||
| 11/26/2021 | TCU (5-7,3-6) | 14 | at | Iowa State | 48 | |||
| 12/29/2021 | Clemson (10-3) | 20 | vs | Iowa State | 13 | Cheez-It Bowl - Orlando FL | ACC |
| vs Iowa State | vs Other Opponents | Iowa State compared to OOs | |
| Record: | 6-7 | 90-64 | |
| Points Scored: | 20.54 | 28.79 | 8.25 |
| Points Allowed: | 31.31 | 24.56 | 6.75 |
| Margin: | -10.77 | 4.23 | 15.00 |
| Total Points: | 51.85 | 53.35 | -1.50 |