| 1 | Mon Nov 4 | vs Morehead St | W93-45 | 1-0 | 1.000 | - | ESPN+ | KFC Yum! Center · Louisville, KY |
| 2 | Sat Nov 9 | vs #12Tennessee | L55-77 | 1-1 | .500 | - | ACC Network | KFC Yum! Center · Louisville, KY |
| 3 | Tue Nov 19 | vs Bellarmine | W100-68 | 2-1 | .667 | - | ESPN+ | KFC Yum! Center · Louisville, KY |
| 4 | Fri Nov 22 | vs Winthrop | W76-61 | 3-1 | .750 | - | ESPN+ | KFC Yum! Center · Louisville, KY |
| 5 | Wed Nov 27 | at #14Indiana | W89-61 | 4-1 | .800 | - | ESPN | Simon Skjodt Assembly Hall · Bloomington, IN |
| 6 | Thu Nov 28 | vs West Virginia | W79-70 (OT) | 5-1 | .833 | - | ESPN | KFC Yum! Center · Louisville, KY |
| 7 | Fri Nov 29 | vs Oklahoma | L64-69 | 5-2 | .714 | - | ESPN | KFC Yum! Center · Louisville, KY |
| 8 | Tue Dec 3 | vs #23Ole Miss | L63-86 | 5-3 | .625 | - | ACC Network | KFC Yum! Center · Louisville, KY |
| 9 | Sun Dec 8 | vs #9Duke | L65-76 | 5-4 | .556 | - | ACC Network | KFC Yum! Center · Louisville, KY |
| 10 | Wed Dec 11 | vs UTEP | W77-74 | 6-4 | .600 | - | ESPN+ | KFC Yum! Center · Louisville, KY |
| 11 | Sat Dec 14 | at #5Kentucky | L85-93 | 6-5 | .545 | - | ESPN | Rupp Arena · Lexington, KY |
| 12 | Sat Dec 21 | at Florida St | W90-76 | 7-5 | .583 | - | The CW Network | Donald L. Tucker Center · Tallahassee, FL |
| 13 | Sat Dec 28 | vs E Kentucky | W78-76 | 8-5 | .615 | - | The CW Network | KFC Yum! Center · Louisville, KY |
| 14 | Wed Jan 1 | vs UNC | W83-70 | 9-5 | .643 | - | ACC Network | KFC Yum! Center · Louisville, KY |
| 15 | Sat Jan 4 | at Virginia | W70-50 | 10-5 | .667 | - | ACC Network | John Paul Jones Arena · Charlottesville, VA |
| 16 | Tue Jan 7 | vs Clemson | W74-64 | 11-5 | .688 | - | ESPNU | KFC Yum! Center · Louisville, KY |
| 17 | Sat Jan 11 | at Pitt | W82-78 | 12-5 | .706 | - | ESPN2 | Petersen Events Center · Pittsburgh, PA |
| 18 | Tue Jan 14 | at Syracuse | W85-61 | 13-5 | .722 | - | ACC Network | JMA Wireless Dome · Syracuse, NY |
| 19 | Sat Jan 18 | vsVirginia | W81-67 | 14-5 | .737 | - | ESPN2 | KFC Yum! Center · Louisville, KY |
| 20 | Tue Jan 21 | at SMU | W98-73 | 15-5 | .750 | #25 | ACC Network | Moody Coliseum · Dallas, TX |
| 21 | Tue Jan 28 | vs Wake Forest | W72-59 | 16-5 | .762 | #21 | ACC Network | KFC Yum! Center · Louisville, KY |
| 22 | Sat Feb 1 | at Georgia Tech | L70-77 | 16-6 | .727 | #21 | The CW Network | McCamish Pavilion · Atlanta, GA |
| 23 | Wed Feb 5 | at Boston College | W84-58 | 17-6 | .739 | - | ACC Network | Silvio O. Conte Forum · Chestnut Hill, MA |
| 24 | Sat Feb 8 | vs Miami | W88-78 | 18-6 | .750 | - | ESPN2 | KFC Yum! Center · Louisville, KY |
| 25 | Wed Feb 12 | at NC State | W91-66 | 19-6 | .760 | - | ESPN2 | PNC Arena · Raleigh, NC |
| 26 | Sun Feb 16 | at Notre Dame | W75-60 | 20-6 | .769 | - | ACC Network | Purcell Pavilion · South Bend, IN |
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