Jerry Smith added 16 points for the Cardinals (27-5), who snapped out of a shooting funk from beyond the arc by hitting 13 3-pointers in winning their ninth straight game.
Louisville advanced to play either No. 18 Syracuse or West Virginia and try for its first conference tournament title since 2005, when the school was still a member of Conference USA.
Meanwhile, it was another disappointing tournament for Villanova, which hasn't won consecutive games here since 2004 and hasn't reach the tournament championship since 1997.
Dante Cunningham and Corey Fisher scored 14 each to lead Villanova, but the Wildcats couldn't solve the intense full-court pressure that Louisville coach Rick Pitino slapped on coming out of halftime.
over Villanova Friday night.
The Wildcats wound up turning the ball over 23 times, and six were by veteran guard Scottie Reynolds, who finished 1-for-6 from the field and missed all three of his 3-point attempts in finishing with just two points in 38 minutes.
In the only other meeting between the schools this season, Terrence Williams' driving layup with 7.4 seconds left boosted Louisville to a physical 61-60 win on the road.
That victory proved to be a tremendous momentum-builder for the Cardinals, who'd been struggling to find their identity in early January. They returned home to beat then-No. 13 Notre Dame and topple then-No. 1 Pittsburgh, before beating highly ranked Syracuse the following week.
Suddenly, Pitino's club was a trendy pick to go deep in the NCAA tournament.
They didn't look much like that dominating team in the first half, though, when Cunningham scored at will inside and Villanova slowly built a lead against the regular-season conference champions.
Louisville still trailed 34-26 at halftime, but Andre McGee hit the first of his three 3-pointers less than a minute in, and Smith added another a few seconds later to close the gap.
Reynolds committed two of his turnovers on back-to-back possessions, and after Cunningham briefly slowed the Cardinals' momentum with a basket inside, Smith hit another 3 and a few minutes later buried yet another from in front of the Louisville bench.
He emphatically punched the air as he strutted out near midcourt, capping a 17-2 run that turned Louisville's halftime deficit into a 43-36 lead with 15:14 to go.
The Wildcats, coming off a last-second 76-75 victory over No. 21 Marquette a day earlier, managed to tie it at 50 when Dwyane Anderson scored with just over 8 minutes left.
But the Cardinals had an answer every time, and McGee hit another 3-pointer that triggered a 10-0 run to put Louisville ahead for good.
The Cardinals wound up shooting 51.5 percent from the field in the second half, and hit 8-of-13 3-pointers over the final 20 minutes. That came after they were just 3-of-19 from beyond the arc against Providence in the tournament quarterfinals.