| 9/3/2021 | Old Dominion (6-7) | 10 | at | Wake Forest | 42 | | | CUSA |
| 9/11/2021 | Norfolk State (6-5) | 16 | at | Wake Forest | 41 | | | MEAC (1AA) |
| 9/18/2021 | Florida State (5-7,4-4) | 14 | at | Wake Forest | 35 | | | |
| 9/24/2021 | Wake Forest | 37 | at | Virginia (6-6,4-4) | 17 | | | |
| 10/2/2021 | Louisville (6-7,4-4) | 34 | at | Wake Forest | 37 | | | |
| 10/9/2021 | Wake Forest | 40 | at | Syracuse (5-7,2-6) | 37 | OT | | |
| 10/23/2021 | Wake Forest | 70 | at | Army (9-4) | 56 | | | at Ind |
| 10/30/2021 | Duke (3-9,0-8) | 7 | at | Wake Forest | 45 | | | |
| 11/6/2021 | Wake Forest | 55 | at | North Carolina (6-7,4-5) | 58 | | | |
| 11/13/2021 | North Carolina State (9-3,6-2) | 42 | at | Wake Forest | 45 | | | |
| 11/20/2021 | Wake Forest | 27 | at | Clemson (10-3,6-2) | 48 | | | |
| 11/27/2021 | Wake Forest | 41 | at | Boston College (6-6,2-6) | 10 | | | |
| 12/4/2021 | Pittsburgh (11-3,8-1) | 45 | vs | Wake Forest | 21 | | ACC Championship - Charlotte NC | |
| 12/31/2021 | Wake Forest | 38 | vs | Rutgers (5-8) | 10 | | Gator Bowl - Jacksonville FL | vs B10 |