| 9/4/2021 | Oregon State (7-6) | 21 | at | Purdue | 30 | P12 | ||
| 9/11/2021 | Purdue | 49 | at | Connecticut (1-11) | 0 | at Ind | ||
| 9/18/2021 | Purdue | 13 | at | Notre Dame (11-2) | 27 | at ND | ||
| 9/25/2021 | Illinois (5-7,4-5) | 9 | at | Purdue | 13 | |||
| 10/2/2021 | Minnesota (9-4,6-3) | 20 | at | Purdue | 13 | |||
| 10/16/2021 | Purdue | 24 | at | Iowa (10-4,7-3) | 7 | |||
| 10/23/2021 | Wisconsin (9-4,6-3) | 30 | at | Purdue | 13 | |||
| 10/30/2021 | Purdue | 28 | at | Nebraska (3-9,1-8) | 23 | |||
| 11/6/2021 | Michigan State (11-2,7-2) | 29 | at | Purdue | 40 | |||
| 11/13/2021 | Purdue | 31 | at | Ohio State (11-2,8-1) | 59 | |||
| 11/20/2021 | Purdue | 32 | at | Northwestern (3-9,1-8) | 14 | |||
| 11/27/2021 | Indiana (2-10,0-9) | 7 | at | Purdue | 44 | |||
| 12/30/2021 | Tennessee (7-6) | 45 | vs | Purdue | 48 | OT | Music City Bowl - Nashville TN | SEC |
| vs Purdue | vs Other Opponents | Purdue compared to OOs | |
| Record: | 4-9 | 85-67 | |
| Points Scored: | 22.38 | 27.97 | 5.59 |
| Points Allowed: | 29.08 | 24.11 | 4.97 |
| Margin: | -6.70 | 3.86 | 10.56 |
| Total Points: | 51.46 | 52.08 | -0.62 |