Schedule:
| Game | Date | Away Team (Rank) | Away Score | Home Team (Rank) | Home Score | Game Status | Result | Margin |
|---|---|---|---|---|---|---|---|---|
| 1 | 2021-09-02 | East Carolina | 19 | Appalachian State | 33 | Final | L | -14 |
| 2 | 2021-09-11 | South Carolina | 20 | East Carolina | 17 | Final | L | -3 |
| 3 | 2021-09-18 | East Carolina | 42 | Marshall | 38 | Final | W | 4 |
| 4 | 2021-09-25 | Charleston Southern | 28 | East Carolina | 31 | Final | W | 3 |
| 5 | 2021-10-02 | Tulane | 29 | East Carolina | 52 | Final | W | 23 |
| 6 | 2021-10-09 | East Carolina | 16 | Central Florida | 20 | Final | L | -4 |
| 7 | 2021-10-23 | East Carolina | 24 | Houston | 31 | Final(OT) | L | -7 |
| 8 | 2021-10-28 | South Florida | 14 | East Carolina | 29 | Final | W | 15 |
| 9 | 2021-11-06 | Temple | 3 | East Carolina | 45 | Final | W | 42 |
| 10 | 2021-11-13 | East Carolina | 30 | Memphis | 29 | Final(OT) | W | 1 |
| 11 | 2021-11-20 | East Carolina | 38 | Navy | 35 | Final | W | 3 |
| 12 | 2021-11-26 | Cincinnati (2) | 35 | East Carolina (61) | 13 | Final | L | -22 |
| 13 | 2021-12-27 | Boston College (80) | 0 | East Carolina (63) | 0 | Cancelled | - | - |