| 9/4/2021 | Keystone (0-10) | 7 | at | Wilkes | 46 | ECFC | ||
| 9/18/2021 | Wilkes | 35 | at | Misericordia (3-6,2-6) | 15 | |||
| 9/25/2021 | Alvernia (0-10,0-8) | 0 | at | Wilkes | 23 | |||
| 10/2/2021 | Stevenson (5-6,5-3) | 14 | at | Wilkes | 21 | |||
| 10/9/2021 | Wilkes | 31 | at | Albright (2-8,1-7) | 28 | |||
| 10/16/2021 | Wilkes | 13 | at | Widener (7-4,5-3) | 30 | |||
| 10/23/2021 | Lebanon Valley (5-5,4-5) | 20 | at | Wilkes | 30 | |||
| 10/30/2021 | Wilkes | 27 | at | Lycoming (8-3,7-2) | 30 | |||
| 11/6/2021 | Delaware Valley (11-1,8-0) | 30 | at | Wilkes | 0 | |||
| 11/13/2021 | Wilkes | 7 | at | King's (5-5,4-5) | 34 |
| vs Wilkes | vs Other Opponents | Wilkes compared to OOs | |
| Record: | 4-6 | 42-52 | |
| Points Scored: | 20.80 | 21.47 | 0.67 |
| Points Allowed: | 23.30 | 24.00 | -0.70 |
| Margin: | -2.50 | -2.53 | -0.03 |
| Total Points: | 44.10 | 45.47 | -1.37 |