Villanova used 15 points from Ryan Arcidiacono and a stifling overall defensive effort to hand reeling Louisville a 73-64 loss in a Big East matchup from the Wells Fargo Center.
JayVaughn Pinkston added 11 points and six rebounds for the Wildcats (12-7, 3-3 Big East), who outscored the fifth-ranked Cardinals 20-11 over the final four minutes to end a streak of three straight conference losses.
"Great win for us. We have such great respect for Louisville, so we know how good they are," said Villanova coach Jay Wright. "I think that team could still win a national championship, and that's why that win means so much to us and I just think that's a great team."
After falling out of the top spot in the polls following Saturday's narrow home loss to Syracuse, Louisville (16-3, 4-2) was held to just 39.7 percent shooting from the field and committed 17 turnovers to receive a second straight setback following an 11-game win streak.
Wayne Blackshear paced the Cardinals with 17 points, while Peyton Siva netted 15 along with a career-high 13 assists and Gorgui Dieng compiled 10 points and nine rebounds.
"It was one of those road games that was tough, they came out and played really hard," said Siva. "It was a tough team, they took it to us.
A tightly contested second half saw the teams tied at 53-53 with under 4 1/2 minutes to go, before the Wildcats took control with strong play on both ends down the stretch.
Achraf Yacoubou's 3-pointer at the 3:57 mark broke the deadlock, and James Bell followed with a triple of his own to stake Villanova to a 59-53 lead.
Siva scored on the ensuing possession to close the gap to four points, but Mouphtaou Yarou hit 1-of-2 from the line for the Wildcats and Arcidiacono made both of his free throws after being fouled following a Siva turnover to make it a 62-55 game with 1:47 left.
Villanova, which went 22-of-29 from the charity stripe on the night, then sealed the victory by sinking all 10 of its foul-shot attempts in the final minute.
The Cardinals started out slowly as well, missing nine of their first 11 field goal tries and falling behind by a 14-7 count following an 8-0 Villanova burst over a near four-minute stretch. A triple by the Wildcats' Tony Chennault shortly afterward put the hosts ahead by double-digits at 23-13 with eight minutes left in the first half.
Louisville bounced back, however, with Stephan Van Treese's 3-point play igniting a 12-0 flurry that sent the Cardinals back in front with just over 4 1/2 minutes left until intermission.
Villanova would head into the break with a 30-28 edge following Pinkston's successful jumper with nine seconds on the clock, and the game continued to be nip-and-tuck over the entirety of the second half.
A 14-3 run capped by a Behanan dunk staked Louisville to a 48-42 lead with 11 minutes left, and the Cardinals were up 52-46 with 8:25 to play before Villanova ripped off seven straight points. Daniel Ochefu tipped in an Arcidiacono miss with 5:51 remaining to send the Wildcats back in front by a 53-52 score.
Siva's previous career high for assists was 12, set in a win over Florida International on Dec. 19 ... Villanova is now 10-2 when holding the opposition to 70 points or less this season ... The Wildcats finished 7-of-15 from 3- point range, improving to 9-0 on the season when making six or more treys in a game ... Russ Smith, Louisville's leading scorer with an average of 19.3 points per game, was held to just eight on 2-of-13 shooting ... Cardinals head coach Rick Pitino fell to 7-9 all-time against Villanova.