| 9/4/2021 | South Carolina State | 41 | at | Alabama A&M (7-3) | 42 | at SWAC | ||
| 9/11/2021 | South Carolina State | 3 | at | Clemson (10-3) | 49 | at ACC | ||
| 9/18/2021 | South Carolina State | 35 | at | New Mexico State (2-10) | 43 | at Ind | ||
| 10/2/2021 | Bethune-Cookman (2-9) | 35 | at | South Carolina State | 42 | SWAC | ||
| 10/9/2021 | South Carolina State | 7 | at | Florida A&M (9-3) | 30 | at SWAC | ||
| 10/16/2021 | Morgan State (2-9,1-4) | 14 | at | South Carolina State | 37 | |||
| 10/23/2021 | South Carolina State | 13 | at | Delaware State (5-6,2-3) | 7 | |||
| 10/30/2021 | South Carolina State | 27 | at | North Carolina Central (6-5,4-1) | 24 | |||
| 11/6/2021 | Howard (3-8,1-4) | 12 | at | South Carolina State | 15 | |||
| 11/13/2021 | North Carolina A&T (5-6) | 27 | at | South Carolina State | 17 | BigS | ||
| 11/20/2021 | South Carolina State | 31 | at | Norfolk State (6-5,2-3) | 21 | |||
| 12/18/2021 | South Carolina State | 31 | vs | Jackson State (11-2) | 10 | Celebration Bowl - Atlanta GA | vs SWAC |
| vs South Carolina State | vs Other Opponents | South Carolina State compared to OOs | |
| Record: | 5-7 | 63-62 | |
| Points Scored: | 26.17 | 25.56 | -0.61 |
| Points Allowed: | 24.92 | 27.11 | -2.19 |
| Margin: | 1.25 | -1.55 | -2.80 |
| Total Points: | 51.09 | 52.67 | -1.58 |