| 9/6/2021 | Louisville | 24 | vs | Mississippi (10-3) | 43 | Atlanta GA | vs SEC | |
| 9/11/2021 | Eastern Kentucky (7-4) | 3 | at | Louisville | 30 | WAC (1AA) | ||
| 9/17/2021 | UCF (9-4) | 35 | at | Louisville | 42 | AAC | ||
| 9/25/2021 | Louisville | 31 | at | Florida State (5-7,4-4) | 23 | |||
| 10/2/2021 | Louisville | 34 | at | Wake Forest (11-3,7-3) | 37 | |||
| 10/9/2021 | Virginia (6-6,4-4) | 34 | at | Louisville | 33 | |||
| 10/23/2021 | Boston College (6-6,2-6) | 14 | at | Louisville | 28 | |||
| 10/30/2021 | Louisville | 13 | at | North Carolina State (9-3,6-2) | 28 | |||
| 11/6/2021 | Clemson (10-3,6-2) | 30 | at | Louisville | 24 | |||
| 11/13/2021 | Syracuse (5-7,2-6) | 3 | at | Louisville | 41 | |||
| 11/18/2021 | Louisville | 62 | at | Duke (3-9,0-8) | 22 | |||
| 11/27/2021 | Kentucky (10-3) | 52 | at | Louisville | 21 | SEC | ||
| 12/28/2021 | Air Force (10-3) | 31 | vs | Louisville | 28 | First Responder Bowl - Dallas TX | MW |
| vs Louisville | vs Other Opponents | Louisville compared to OOs | |
| Record: | 7-6 | 94-55 | |
| Points Scored: | 27.31 | 30.56 | 3.25 |
| Points Allowed: | 31.62 | 24.40 | 7.22 |
| Margin: | -4.31 | 6.16 | 10.47 |
| Total Points: | 58.93 | 54.96 | 3.97 |