| 1 | Tue Nov 5 | at Miami | W87-74 | 1-0 | 1.000 | #5 | ACC Network | Watsco Center · Coral Gables, FL |
| 2 | Sun Nov 10 | vsYoungstown St | W78-55 | 2-0 | 1.000 | - | | KFC Yum! Center · Louisville, KY |
| 3 | Wed Nov 13 | vsIndiana St | W91-62 | 3-0 | 1.000 | #4 | ACC Network | KFC Yum! Center · Louisville, KY |
| 4 | Sun Nov 17 | vsNC Central | W87-58 | 4-0 | 1.000 | - | ACC Network | KFC Yum! Center · Louisville, KY |
| 5 | Wed Nov 20 | vsSC Upstate | W76-50 | 5-0 | 1.000 | - | ACC Network | KFC Yum! Center · Louisville, KY |
| 6 | Sun Nov 24 | vsAkron | W82-76 | 6-0 | 1.000 | - | ACC Network | KFC Yum! Center · Louisville, KY |
| 7 | Fri Nov 29 | atWestern KY | W71-54 | 7-0 | 1.000 | #2 | | E. A. Diddle Arena · Bowling Green, KY |
| 8 | Tue Dec 3 | vsMichigan | W58-43 | 8-0 | 1.000 | - | ESPN | KFC Yum! Center · Louisville, KY |
| 9 | Fri Dec 6 | vsPitt | W64-46 | 9-0 | 1.000 | #1 | ACC Network | KFC Yum! Center · Louisville, KY |
| 10 | Tue Dec 10 | vsTexas Tech | L57-70 | 9-1 | .900 | - | ESPN | KFC Yum! Center · Louisville, KY |
| 11 | Sat Dec 14 | vsE Kentucky | W99-67 | 10-1 | .909 | #1 | ACC Network | KFC Yum! Center · Louisville, KY |
| 12 | Wed Dec 18 | vsMiami OH | W70-46 | 11-1 | .917 | #3 | ACC Network | KFC Yum! Center · Louisville, KY |
| 13 | Sat Dec 28 | at19Kentucky | L70-78 (OT) | 11-2 | .846 | #3 | CBS | Rupp Arena · Lexington, KY |
| 14 | Sat Jan 4 | vs18Florida St | L65-78 | 11-3 | .786 | #7 | ESPN2 | KFC Yum! Center · Louisville, KY |
| 15 | Tue Jan 7 | vsMiami | W74-58 | 12-3 | .800 | #13 | ESPN2 | KFC Yum! Center · Louisville, KY |
| 16 | Sat Jan 11 | atNotre Dame | W67-64 | 13-3 | .813 | #13 | ESPN | Purcell Pavilion · South Bend, IN |
| 17 | Tue Jan 14 | atPitt | W73-68 (OT) | 14-3 | .824 | #11 | ACC Network | Petersen Events Center · Pittsburgh, PA |
| 18 | Sat Jan 18 | at3Duke | W79-73 | 15-3 | .833 | #11 | ESPN | Cameron Indoor Stadium · Durham, NC |
| 19 | Wed Jan 22 | vsGeorgia Tech | W68-64 | 16-3 | .842 | #6 | | KFC Yum! Center · Louisville, KY |
| 20 | Sat Jan 25 | vsClemson | W80-62 | 17-3 | .850 | #6 | | KFC Yum! Center · Louisville, KY |
| 21 | Wed Jan 29 | atBoston College | W86-69 | 18-3 | .857 | #6 | ACC Network | Silvio O. Conte Forum · Chestnut Hill, MA |
| 22 | Sat Feb 1 | atNC State | W77-57 | 19-3 | .864 | #6 | ESPN | PNC Arena · Raleigh, NC |
| 23 | Wed Feb 5 | vsWake Forest | W86-76 | 20-3 | .870 | #5 | ESPN2 | KFC Yum! Center · Louisville, KY |
| 24 | Sat Feb 8 | vsVirginia | W80-73 | 21-3 | .875 | #5 | ESPN | KFC Yum! Center · Louisville, KY |
| 25 | Wed Feb 12 | atGeorgia Tech | L58-64 | 21-4 | .840 | #5 | ACC Network | McCamish Pavilion · Atlanta, GA |
| 26 | Sat Feb 15 | atClemson | L62-77 | 21-5 | .808 | #5 | ACC Network | Littlejohn Coliseum · Clemson, SC |
| 27 | Wed Feb 19 | vsSyracuse | W90-66 | 22-5 | .815 | #11 | ESPN | KFC Yum! Center · Louisville, KY |
| 28 | Sat Feb 22 | vsUNC | W72-55 | 23-5 | .821 | #11 | ESPN | KFC Yum! Center · Louisville, KY |
| 29 | Mon Feb 24 | at6Florida St | L67-82 | 23-6 | .793 | #11 | ESPN | Donald L. Tucker Center · Tallahassee, FL |
| 30 | Sun Mar 1 | vsVirginia Tech | W68-52 | 24-6 | .800 | #11 | ACC Network | KFC Yum! Center · Louisville, KY |
| 31 | Sat Mar 7 | at22Virginia | L54-57 | 24-7 | .774 | #10 | ESPN | John Paul Jones Arena · Charlottesville, VA |
