| 9/2/2021 | Mississippi Valley State (4-7) | 0 | at | Murray State | 35 | SWAC | ||
| 9/11/2021 | Murray State | 7 | at | Cincinnati (13-1) | 42 | at AAC | ||
| 9/18/2021 | Murray State | 10 | at | Bowling Green (4-8) | 27 | at MAC | ||
| 10/2/2021 | Eastern Illinois (1-10,1-6) | 6 | at | Murray State | 22 | |||
| 10/9/2021 | Murray State | 24 | at | Tennessee-Martin (10-3,6-1) | 48 | |||
| 10/16/2021 | Murray State | 32 | at | SE Missouri State (4-7,4-4) | 31 | |||
| 10/23/2021 | Austin Peay (6-5,4-3) | 47 | at | Murray State | 6 | |||
| 10/30/2021 | Murray State | 21 | at | Tennessee State (5-6,4-3) | 27 | |||
| 11/6/2021 | Tennessee Tech (3-8,1-5) | 27 | at | Murray State | 32 | |||
| 11/13/2021 | SE Missouri State (4-7,4-4) | 10 | at | Murray State | 28 | |||
| 11/20/2021 | Murray State | 20 | at | Eastern Illinois (1-10,1-6) | 13 |
| vs Murray State | vs Other Opponents | Murray State compared to OOs | |
| Record: | 5-6 | 50-62 | |
| Points Scored: | 25.27 | 24.93 | -0.34 |
| Points Allowed: | 21.55 | 29.05 | -7.50 |
| Margin: | 3.72 | -4.12 | -7.84 |
| Total Points: | 46.82 | 53.98 | -7.16 |