The short-handed Cardinals (14-4, 2-3 Big East) needed Smith's performance to register just their second win in six games.
Chris Smith added 20 points and Gorgui Dieng contributed 13 points to go with 14 rebounds to help hand Louisville a morale-boosting victory.
The Blue Demons (10-7, 1-4) fell to their third loss despite a team-high 14 points from Brandon Young.
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