Jerry Smith added 14 points while Samardo Samuels chipped in 13 points as the Cardinals (14-8, 5-4 Big East) bounced back from a potentially devastating loss at West Virginia on Saturday with arguably their biggest win of the season.
Louisville never trailed and built a 19-point lead early in the second half before holding off a couple of mild runs by the Huskies.
Jerome Dyson led UConn (13-9, 3-6) with 18 points and Stanley Robinson had 14 points and 11 rebounds but the Huskies fell to 2-3 without coach Jim Calhoun, who is on indefinite medical leave. The Huskies have lost six of their last eight overall.
UConn shot just 38 percent from the field and turned it over 18 times to put a serious dent in their NCAA Tournament hopes.