Peyton Siva helped spark a big comeback with 11 points and eight assists for Louisville (29-5), which rallied from a 16-point deficit with a 27-3 second-half run.
Russ Smith and Luke Hancock netted 10 points apiece as the Cardinals made a case for the No. 1 overall seed in the NCAA Tournament.
The game was the last-ever contest in the storied Big East basketball tournament at Madison Square Garden. Seven of the conference's basketball-playing schools are leaving after this season.
The Orange (26-9), who will land an at-large berth to the NCAA Tournament, were led by C.J. Fair with 21 points.