The win didn't come easily for the Wildcats, who overcame their own sloppy play against the Orange defensive pressure down the stretch. Syracuse, however, missed six shots in the final minute, including three 3-point attempts in the final 8 seconds before the buzzer sounded as Jonny Flynn's shot from the left corner bounced off the rim.
Shane Clark and Dwayne Anderson both scored 20 points for the Wildcats (22-5, 10-4 Big East), who won for the eighth time in nine games.
Eric Devendorf scored 22 points for Syracuse (19-8, 7-7), which dropped to 2-6 in its last eight.
The loss kept Orange coach Jim Boeheim from passing Dean Smith to become the first coach to register 31 20-win seasons at the Division I level.
Villanova, meanwhile, all but secured a spot among the top five teams in the heavily contested Big East standings, moving three wins ahead of Syracuse, which dropped into a ninth-place tie with Cincinnati.
The Wildcats led for most of the game, and never trailed after taking control with an 11-0 run over a 2:30 span midway through the second half.
The rally came immediately after Syracuse enjoyed a 14-2 run to take a 59-57 lead when Flynn set up Andy Rautins for an open 3-pointer in the right corner.
Anderson broke a 59-tie with a 3-pointer with 11:27 left. A little over a minute later, Anderson capped a 9-0 run with a dunk on a transition break following Flynn's second consecutive turnover at the other end.
The end had its nail-biting moments, but the Orange couldn't find the basket after Devendorf hit a 3-pointer and followed with a layup cutting the Wildcats' lead to 88-86 with 16.5 seconds left.
After Reggie Redding hit one of two free throws, the Orange missed their final four attempts.
The Orange have lost five straight against ranked opponents, and dropped to 14-3 at home this season.
Villanova defeated Syracuse for the fifth time in six meetings and swept the season series for the first time since 2005-06.