Smith hit a trio of 3-pointers and grabbed five rebounds for the Cardinals (17-4, 5-3 Big East), who avoided their first four-game skid since 2004.
Gorgui Dieng contributed 14 points with 12 rebounds and sank two game-clinching free throws to secure the victory.
Chane Behanan also reached double figures with 12 points for Louisville, which played without injured starting forward Wayne Blackshear.
The Panthers (17-5, 5-4) were led Tray Woodall with 14 points.
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