| 9/4/2021 | East Tennessee St | 23 | at | Vanderbilt (2-10) | 3 | at SEC | ||
| 9/11/2021 | Virginia-Wise (5-6) | 14 | at | East Tennessee St | 45 | SAC (D2) | ||
| 9/18/2021 | Delaware State (5-6) | 6 | at | East Tennessee St | 38 | MEAC | ||
| 9/25/2021 | East Tennessee St | 55 | at | Samford (4-7,3-5) | 48 | OT | ||
| 10/2/2021 | Wofford (1-10,0-8) | 21 | at | East Tennessee St | 27 | |||
| 10/9/2021 | The Citadel (4-7,3-5) | 21 | at | East Tennessee St | 48 | |||
| 10/16/2021 | East Tennessee St | 16 | at | Chattanooga (6-5,5-3) | 21 | |||
| 10/23/2021 | East Tennessee St | 17 | at | Furman (6-5,4-4) | 13 | |||
| 11/6/2021 | VMI (6-5,4-4) | 20 | at | East Tennessee St | 27 | |||
| 11/13/2021 | East Tennessee St | 56 | at | Western Carolina (4-7,4-4) | 35 | |||
| 11/20/2021 | Mercer (7-3,6-2) | 35 | at | East Tennessee St | 38 | |||
| 12/4/2021 | Kennesaw St (11-2) | 31 | at | East Tennessee St | 32 | BigS | ||
| 12/11/2021 | East Tennessee St | 3 | at | North Dakota State (14-1) | 27 | FCS quarterfinals | at MVC |
| vs East Tennessee St | vs Other Opponents | East Tennessee St compared to OOs | |
| Record: | 2-11 | 73-63 | |
| Points Scored: | 22.69 | 28.40 | 5.71 |
| Points Allowed: | 32.69 | 27.21 | 5.48 |
| Margin: | -10.00 | 1.19 | 11.19 |
| Total Points: | 55.38 | 55.61 | -0.23 |