Ryan Arcidiacono sank the final two free throws with 6 seconds on the clock to ice the victory for the Wildcats (13-7, 4-3 Big East), and hand Syracuse (18-2, 6-1) its first conference loss.
Arcidiacono, who had 10 points in the game, also dropped in a clutch 3-pointer for Villanova that sent the game into OT. Darrun Hilliard led the Wildcats with 25 points, three in the overtime period, and five rebounds.
Brandon Triche led the Orange with 24 points and Michael Carter-Williams added 16.
Villanova led 32-26 at halftime but were outscored 35-29 in the second half. The Wildcats rallied to tie the game when Syracuse failed to score in the final 3:37 of regulation.