Head Coach: Jeff Walz Record: 29-5 (15-2 ACC)
| Date | Site | Opp AP | Opponent | W/L | UL | Opp | OT | TV | Overall | Conf | Attendance | City | State | Arena | Event |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 11/04/2021 | H | Union, Tenn. (Exhibition) | W | 106 | 32 | 6,587 | Louisville | Ky. | KFC Yum! Center | ||||||
| 11/12/2021 | N | 22 | Arizona | L | 59 | 61 | OT | ESPNU | 0-1 | 0-0 | 2,345 | Sioux Falls | S.D. | Sanford Pentagon | 2021 The Invitational |
| 11/16/2021 | H | Bellarmine | W | 82 | 25 | ACCNX | 1-1 | 0-0 | 7,014 | Louisville | Ky. | KFC Yum! Center | |||
| 11/17/2021 | H | Tennessee-Martin | W | 62 | 30 | ACCNX | 2-1 | 0-0 | 6,809 | Louisville | Ky. | KFC Yum! Center | |||
| 11/20/2021 | A | Washington | W | 61 | 53 | Pac-12+ | 3-1 | 0-0 | 1,884 | Seattle | Wash. | Alaska Airlines Arena | |||
| 11/23/2021 | A | Cal Poly | W | 72 | 32 | ESPN+ | 4-1 | 0-0 | 662 | San Luis Obispo | Calif. | Mott Athletics Center | |||
| 11/28/2021 | A | Colorado State | W | 71 | 56 | Mountain West Network | 5-1 | 0-0 | 1,336 | Fort Collins | Colo. | Moby Arena | |||
| 12/02/2021 | H | 12 | Michigan | W | 70 | 48 | ESPN | 6-1 | 0-0 | 7,309 | Louisville | Ky. | KFC Yum! Center | 2021 ACC/Big 10 Challenge | |
| 12/05/2021 | H | Belmont | W | 80 | 66 | ACCN | 7-1 | 0-0 | 7,092 | Louisville | Ky. | KFC Yum! Center | |||
| 12/12/2021 | H | 14 | Kentucky | W | 64 | 58 | ESPN | 8-1 | 0-0 | 12,167 | Louisville | Ky. | KFC Yum! Center | 2021 Jimmy V Classic | |
| 12/16/2021 | H | Eastern Kentucky | W | 82 | 38 | ACCN | 9-1 | 0-0 | 6,937 | Louisville | Ky. | KFC Yum! Center | |||
| 12/19/2021 | N | 7 | Connecticut | W | 69 | 64 | ESPN | 10-1 | 0-0 | 8,204 | Uncasville | Conn. | Mohegan Sun Arena | 2021 Jimmy V Classic | |
| 12/30/2021 | H | Boston College | W | 79 | 49 | ACCNX | 11-1 | 1-0 | 7,709 | Louisville | Ky. | KFC Yum! Center | |||
| 01/02/2022 | A | 16 | Georgia Tech | W | 50 | 48 | ACCN | 12-1 | 2-0 | 1,918 | Atlanta | Ga. | McCamish Pavilion | ||
| 01/06/2022 | H | Pittsburgh | W | 81 | 39 | ACCN | 13-1 | 3-0 | 6,703 | Louisville | Ky. | KFC Yum! Center | |||
| 01/13/2022 | H | Syracuse | W | 84 | 71 | ACCNX | 14-1 | 4-0 | 7,307 | Louisville | Ky. | KFC Yum! Center | |||
| 01/16/2022 | A | Boston College | W | 63 | 53 | ACCN | 15-1 | 5-0 | 1,066 | Boston | Mass. | Conte Forum | |||
| 01/20/2022 | A | 4 | North Carolina State | L | 59 | 68 | ESPN | 15-2 | 5-1 | 5,500 | Raleigh | N.C. | Reynolds Coliseum | ||
| 01/23/2022 | H | Wake Forest | W | 72 | 60 | ACCN | 16-2 | 6-1 | 8,802 | Louisville | Ky. | KFC Yum! Center | |||
| 01/27/2022 | H | Florida State | W | 75 | 62 | ACCN | 17-2 | 7-1 | 7,755 | Louisville | Ky. | KFC Yum! Center | |||
| 01/30/2022 | H | 21 | Duke | W | 77 | 65 | ESPN | 18-2 | 8-1 | 9,001 | Louisville | Ky. | KFC Yum! Center | ||
| 02/01/2022 | A | Miami, Fla. | W | 69 | 66 | ACCNX | 19-2 | 9-1 | Coral Gables | Fla. | Watsco Center | ||||
| 02/03/2022 | A | Clemson | W | 93 | 71 | Bally Sports South | 20-2 | 10-1 | 493 | Clemson | S.C. | Littlejohn Coliseum | |||
| 02/06/2022 | A | Syracuse | W | 100 | 64 | Bally Sports South | 21-2 | 11-1 | 1,401 | Syracuse | N.Y. | Carrier Dome | |||
| 02/13/2022 | H | 18 | Notre Dame | W | 73 | 47 | ESPN | 22-2 | 12-1 | 10,056 | Louisville | Ky. | KFC Yum! Center | ||
| 02/17/2022 | A | 24 | North Carolina | L | 65 | 66 | RSN | 22-3 | 12-2 | 2,115 | Chapel Hill | N.C. | Carmichael Arena | ||
| 02/20/2022 | H | 23 | Virginia Tech | W | 70 | 56 | ACCN | 23-3 | 13-2 | 10,294 | Louisville | Ky. | KFC Yum! Center | ||
| 02/24/2022 | A | Pittsburgh | W | 66 | 55 | ACCNX | 24-3 | 14-2 | 1,344 | Pittsburgh | Pa. | Petersen Events Center | |||
| 02/27/2022 | A | 14 | Notre Dame | W | 86 | 64 | ESPN2 | 25-3 | 15-2 | 7,531 | Notre Dame | Ind. | Purcell Pavilion at the Joyce Center | ||
| 03/04/2022 | N | Miami, Fla. | L | 59 | 61 | Bally Sports South | 25-4 | 15-2 | Greensboro | N.C. | Greensboro Coliseum Complex | 2022 ACC Tournament | |||
| 03/18/2022 | H | Albany | W | 83 | 51 | ESPN2 | 26-4 | 15-2 | 8,407 | Louisville | Ky. | KFC Yum! Center | 2022 NCAA Tournament First Round | ||
| 03/20/2022 | H | Gonzaga | W | 68 | 59 | ESPN | 27-4 | 15-2 | 10,414 | Louisville | Ky. | KFC Yum! Center | 2022 NCAA Tournament Second Round | ||
| 03/26/2022 | N | 18 | Tennessee | W | 76 | 64 | ESPN2 | 28-4 | 15-2 | Wichita | Kan. | Intrust Bank Arena | 2022 NCAA Tournament Sweet Sixteen | ||
| 03/28/2022 | N | 12 | Michigan | W | 62 | 50 | ESPN | 29-4 | 15-2 | 4,695 | Wichita | Kan. | Intrust Bank Arena | 2022 NCAA Tournament Elite Eight | |
| 04/01/2022 | N | 1 | South Carolina | L | 59 | 72 | ESPN | 29-5 | 15-2 | Minneapolis | Minn. | Target Center | 2022 NCAA Tournament Final Four |