Head Coach: Jeff Walz Record: 26-4 (14-2 ACC)
| Date | Site | Opp AP | Opponent | W/L | UL | Opp | TV | Overall | Conf | Attendance | City | State | Event |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 11/25/2020 | A | Southeast Missouri State | W | 74 | 53 | ESPN+ | 1-0 | 0-0 | 475 | Show Me Center -- Cape Girardeau | Mo. | ||
| 11/29/2020 | H | Eastern Kentucky | W | 101 | 58 | ACCNX | 2-0 | 0-0 | 2,614 | Louisville | Ky. | ||
| 12/04/2020 | N | 20 | DePaul | W | 116 | 75 | ESPN | 3-0 | 0-0 | Montville | Conn. | 2020 Jimmy V Classic | |
| 12/06/2020 | H | Tennessee-Martin | W | 85 | 67 | ACC Network | 4-0 | 0-0 | 2,709 | Louisville | Ky. | ||
| 12/09/2020 | A | Duke | W | 73 | 49 | Fox Sports South/Fox Sports Ohio/RSN | 5-0 | 1-0 | Durham | N.C. | |||
| 01/01/2021 | H | Northern Kentucky | W | 74 | 64 | ACCNX | 6-0 | 1-0 | Louisville | Ky. | |||
| 01/02/2021 | H | Bellarmine | W | 97 | 46 | ACCNX | 7-0 | 1-0 | 2,718 | Louisville | Ky. | ||
| 01/05/2021 | H | Tennessee-Martin | W | 96 | 61 | ACC Network | 8-0 | 1-0 | 2,754 | Louisville | Ky. | ||
| 01/07/2021 | A | Virginia Tech | W | 71 | 67 | RSN | 9-0 | 2-0 | 250 | Blacksburg | Va. | ||
| 01/10/2021 | H | Clemson | W | 70 | 45 | ACC Network | 10-0 | 3-0 | 2,734 | Louisville | Ky. | ||
| 01/14/2021 | H | Boston College | W | 89 | 70 | ACC Network | 11-0 | 4-0 | 2,604 | Louisville | Ky. | ||
| 01/17/2021 | H | Florida State | W | 84 | 56 | ESPN2 | 12-0 | 5-0 | 2,804 | Louisville | Ky. | ||
| 01/21/2021 | H | 23 | Syracuse | W | 67 | 54 | ESPN2 | 13-0 | 6-0 | 2,643 | Louisville | Ky. | |
| 01/24/2021 | A | Wake Forest | W | 65 | 63 | ACC Network | 14-0 | 7-0 | Winston-Salem | N.C. | |||
| 01/26/2021 | H | Miami, Fla. | W | 79 | 76 | ACC Network | 15-0 | 8-0 | 2,653 | Louisville | Ky. | ||
| 01/28/2021 | H | North Carolina | W | 79 | 68 | ACC Network | 16-0 | 9-0 | 2,748 | Louisville | Ky. | ||
| 02/01/2021 | H | 4 | North Carolina State | L | 60 | 74 | ESPN | 16-1 | 9-1 | 3,201 | Louisville | Ky. | |
| 02/04/2021 | A | Boston College | W | 97 | 68 | ACC Network | 17-1 | 10-1 | Boston | Mass. | |||
| 02/07/2021 | H | Notre Dame | W | 71 | 65 | ESPN | 18-1 | 11-1 | 2,912 | Louisville | Ky. | ||
| 02/11/2021 | H | Georgia Tech | W | 85 | 70 | ACCNX | 19-1 | 12-1 | 2,914 | Louisville | Ky. | ||
| 02/18/2021 | A | Pittsburgh | W | 82 | 58 | ACCN | 20-1 | 13-1 | 500 | Pittsburgh | Pa. | ||
| 02/21/2021 | A | Florida State | L | 59 | 68 | ACCNX | 20-2 | 13-2 | 1,258 | Tallahassee | Fla. | ||
| 02/28/2021 | A | Notre Dame | W | 78 | 61 | ESPN | 21-2 | 14-2 | 126 | Notre Dame | Ind. | ||
| 03/05/2021 | N | Wake Forest | W | 65 | 53 | RSN | 22-2 | 14-2 | 2021 ACC Tournament | ||||
| 03/06/2021 | N | Syracuse | W | 72 | 59 | ACCN | 23-2 | 14-2 | 2021 ACC Tournament | ||||
| 03/07/2021 | N | 3 | North Carolina State | L | 56 | 58 | ESPN2 | 23-3 | 14-2 | 2,063 | 2021 ACC Tournament | ||
| 03/22/2021 | N | Marist | W | 74 | 43 | ESPN | 24-3 | 14-2 | San Antonio | Texas | 2021 NCAA Tournament First Round | ||
| 03/24/2021 | N | Northwestern | W | 62 | 53 | ESPN2 | 25-3 | 14-2 | San Antonio | Texas | 2021 NCAA Tournament Second Round | ||
| 03/28/2021 | N | 23 | Oregon | W | 60 | 42 | ESPN | 26-3 | 14-2 | San Antonio | Texas | 2021 NCAA Tournament Sweet Sixteen | |
| 03/30/2021 | N | 2 | Stanford | L | 63 | 78 | ESPN | 26-4 | 14-2 | 1,463 | San Antonio | Texas | 2021 NCAA Tournament Elite Eight |