Archaf Yacoubou drained a three-pointer with four minutes remaining to break a tie at 53, and James Bell hit a three of his own 51 seconds later to help the Wildcats secure the victory.
Villanova can look at the end of the game to see how they pulled off the upset, but the Wildcats should really trace back to the first frame to see where the game was won.
The Cats got the faithful rocking when Tony Chenault followed up a thunderous dunk by Daniel Ochefu with a three-pointer to give Villanova a 10-point lead midway through the first half. But Villanova didnt keep its foot on the gas.
The Cardinals began to shake their early shooting woes and turned up the full-court pressure defensively to the tune of a 12-0 run to get back in the game.
The Wildcats went nearly five minutes without a point but were able to regroup late in the half and take a 30-28 lead into intermission.
Teams typically wilt after runs like that from top-tier squads like Louisville. The Wildcats proved to be anything but typical on this night.
Wayne Blackshear scored 17 points for Louisville. Peyton Siva scored 15 points and handed out 11 assists.
Inside the box score
Villanova, which leads the Big East in turnovers with 16.3 per game, gave the ball away 19 times. Louisville came into Tuesday forcing the second-most turnovers per game in the nation at 19.7 a game.
Villanova shot 22 of 48 (45.8 percent) from the field and 7 of 15 from three-point range.
Louisville was a dismal 12 of 24 from the free-throw line.
Louisville's Russ Smith -- the Big Easts third-leading scorer with 19.3 points per game -- scored just eight points on 2-of-13 shooting.
When was the last time
Tuesday might marked the 18th meeting between the two schools. The Wildcats win tied the series at nine apiece.
Villanova is now 4-1 against Louisville in games played at the Wells Fargo Center.
Villanovas run against stiff competition continues on Saturday when the Wildcats face No. 3 Syracuse back at the Wells Fargo Center at 11 a.m..
The Wildcats were handed a 72-61 defeat by the Orange at the Carrier Dome back on Jan. 12 to snap their seven-game win streak.