Julius Randle added 17 points for the Wildcats (10-3), who went on a 13-3 run midway through the final 20 minutes to put away their intrastate rivals and claim a third victory in four games.
They made the surge without the star freshman, who left with cramping early in the second half.
Aaron Harrison netted 10 points.
The Cardinals (11-2) got 19 points from Russ Smith but couldn't avoid their first loss since Nov. 24 to North Carolina.
Chris Jones supplied 18 for Louisville.
Ray Liotta sues skin care company over use of likeness
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