Peyton Siva helped out with 13 points as Louisville (26-5, 14-4 Big East) never trailed en route to a seventh straight win to wrap up the regular season.
The last time the Cardinals lost was to the Fighting Irish in a five-overtime epic Feb. 9 in South Bend.
The victory assures them the No. 2 seed in next week's Big East Tournament.
Notre Dame (23-8, 11-7) could manage just 39.3 percent shooting from the field as Jerian Grant went just 2-of-12 from the floor to end with eight points.
The setback relegated the Fighting Irish to a sixth seed in the Big East tourney.
Notable deaths of 2014 [PHOTOS]