JayVaughn Pinkston supplied 13 points and seven rebounds as the Wildcats (12-7, 3-3 Big East) outscored Louisville 20-11 in the closing minutes to break a three-game skid.
Villanova clamped down hard on defense en route to the triumph, holding the Cardinals just 39.7 percent shooting from the floor.
Wayne Blackshear scored 17 points for Louisville (16-3, 4-2), which turned the ball over 17 times while dropping a second straight contest.
Peyton Siva (15 points, 11 assists) and Gorgui Dieng (10, 10 rebounds) each notched a double-double in the defeat.
Notable deaths of 2014 [PHOTOS]