13 games
| Date | Site | Opp AP | Opponent | UL AP | W/L | UL | Opp | OT | Overall | Conf | Attendance | City | State | Stadium | Event |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 09/06/2021 | N | Mississippi | L | 24 | 43 | 0-1 | 30,709 | Atlanta | Ga. | Mercedes-Benz Stadium | Chick-fil-A Kickoff Game | ||||
| 09/11/2021 | H | Eastern Kentucky | W | 30 | 3 | 1-1 | 39,673 | Louisville | Ky. | Cardinal Stadium | |||||
| 09/17/2021 | H | Central Florida | W | 42 | 35 | 2-1 | 39,022 | Louisville | Ky. | Cardinal Stadium | |||||
| 09/25/2021 | A | Florida State | W | 31 | 23 | 3-1 | 1-0 | 50,964 | Tallahassee | Fla. | Doak Campbell Stadium | ||||
| 10/02/2021 | A | 24 | Wake Forest | L | 34 | 37 | 3-2 | 1-1 | 29,077 | Winston-Salem | N.C. | Truist Field | |||
| 10/09/2021 | H | Virginia | L | 33 | 34 | 3-3 | 1-2 | 40,320 | Louisville | Ky. | Cardinal Stadium | ||||
| 10/23/2021 | H | Boston College | W | 28 | 14 | 4-3 | 2-2 | 38,202 | Louisville | Ky. | Cardinal Stadium | ||||
| 10/30/2021 | A | North Carolina State | L | 13 | 28 | 4-4 | 2-3 | 53,123 | Raleigh | N.C. | Carter-Finley Stadium | ||||
| 11/06/2021 | H | Clemson | L | 24 | 30 | 4-5 | 2-4 | 51,729 | Louisville | Ky. | Cardinal Stadium | ||||
| 11/13/2021 | H | Syracuse | W | 41 | 3 | 5-5 | 3-4 | 43,797 | Louisville | Ky. | Cardinal Stadium | ||||
| 11/18/2021 | A | Duke | W | 62 | 22 | 6-5 | 4-4 | 8,493 | Durham | N.C. | Brooks Field at Wallace Wade Stadium | ||||
| 11/27/2021 | H | Kentucky | L | 21 | 52 | 6-6 | 4-4 | 55,018 | Louisville | Ky. | Cardinal Stadium | ||||
| 12/28/2021 | N | Air Force | L | 28 | 31 | 6-7 | 4-4 | 15,251 | Dallas | Texas | Gerald J. Ford Stadium | First Responder Bowl |