| 9/2/2021 | East Carolina (7-5) | 19 | vs | Appalachian State | 33 | Charlotte NC | AAC | |
| 9/11/2021 | Appalachian State | 23 | at | Miami-Florida (7-5) | 25 | at ACC | ||
| 9/18/2021 | Elon (6-5) | 10 | at | Appalachian State | 44 | CAAF (1AA) | ||
| 9/23/2021 | Marshall (7-6) | 30 | at | Appalachian State | 31 | CUSA | ||
| 10/2/2021 | Appalachian State | 45 | at | Georgia State (8-5,6-2) | 16 | |||
| 10/12/2021 | Appalachian State | 13 | at | UL Lafayette (13-1,9-0) | 41 | |||
| 10/20/2021 | Coastal Carolina (11-2,6-2) | 27 | at | Appalachian State | 30 | |||
| 10/30/2021 | UL Monroe (4-8,2-6) | 28 | at | Appalachian State | 59 | |||
| 11/6/2021 | Appalachian State | 48 | at | Arkansas State (2-10,1-7) | 14 | |||
| 11/13/2021 | South Alabama (5-7,2-6) | 7 | at | Appalachian State | 31 | |||
| 11/20/2021 | Appalachian State | 45 | at | Troy (5-7,3-5) | 7 | |||
| 11/27/2021 | Georgia Southern (3-9,2-6) | 3 | at | Appalachian State | 27 | |||
| 12/4/2021 | Appalachian State | 16 | at | UL Lafayette (13-1,9-0) | 24 | Sun Belt Championship | ||
| 12/18/2021 | Western Kentucky (9-5) | 59 | vs | Appalachian State | 38 | Boca Raton Bowl - Boca Raton | CUSA |
| vs Appalachian State | vs Other Opponents | Appalachian State compared to OOs | |
| Record: | 4-10 | 94-66 | |
| Points Scored: | 22.14 | 30.66 | 8.52 |
| Points Allowed: | 34.50 | 26.27 | 8.23 |
| Margin: | -12.36 | 4.39 | 16.75 |
| Total Points: | 56.64 | 56.93 | -0.29 |