| 9/4/2021 | Ashland (5-5) | 35 | at | Notre Dame OH | 42 | OT | | GMAC |
| 9/9/2021 | Notre Dame OH | 31 | at | Wheeling (5-6,5-5) | 15 | | | |
| 9/18/2021 | Notre Dame OH | 51 | at | West Liberty (4-7,4-6) | 10 | | | |
| 9/25/2021 | West Virginia State (6-5,6-4) | 14 | at | Notre Dame OH | 38 | | | |
| 10/2/2021 | Notre Dame OH | 28 | at | Charleston WV (8-2,8-2) | 38 | | | |
| 10/9/2021 | Frostburg State (10-1,9-1) | 21 | at | Notre Dame OH | 23 | | | |
| 10/16/2021 | West Virginia Wesleyan (0-10,0-9) | 14 | at | Notre Dame OH | 52 | | | |
| 10/23/2021 | Notre Dame OH | 34 | at | Glenville State (3-7,3-7) | 14 | | | |
| 10/30/2021 | Fairmont State (5-6,5-5) | 0 | at | Notre Dame OH | 45 | | | |
| 11/6/2021 | Notre Dame OH | 45 | at | UNC Pembroke (5-5,5-4) | 7 | | | |
| 11/13/2021 | Alderson-Broaddus (1-10,1-9) | 7 | at | Notre Dame OH | 72 | | | |
| 11/20/2021 | Slippery Rock (9-3) | 25 | at | Notre Dame OH | 33 | | | PSAC |
| 11/27/2021 | Notre Dame OH | 34 | at | Shepherd (13-2) | 38 | | | at PSAC |