The Wildcats (12-3, 2-2 Big East) trailed by 16 points in the first half and were down seven midway through the second when they went on their game-changing run for yet another big comeback win.
Reynolds sealed the win with a clutch 3-pointer with 30 seconds left that made it 72-66. Reynolds, who was banged up after a baseline collision with a photographer earlier, made two free throws with 13 seconds left to help the Wildcats avoid another upset loss to DePaul.
They evened the season series after the Blue Demons (7-9, 3-2) stunned the Wildcats with an 84-76 win in the conference opener on Jan. 3. DePaul failed to hold on to its early lead built on a surprising succession of wide-open 3-pointers that sucked the life out of the Wildcats crowd.
Draelon Burns scored 27 points and Dar Tucker had 18 for DePaul.
The duo combined to make eight of DePaul's 12 3-pointers, but they had little help from their teammates - no one else scored in double figures.
Pena was sensational during the comeback and gave the Wildcats their first lead of the game, 58-57, on a thunderous dunk with 6:09 remaining. Shane Clark was fouled on a 3-point attempt and made all three free throws and suddenly the Wildcats were in control.
The Blue Demons looked nothing like the team that controlled most of the first 25 minutes.
Will Walker hit two 3s early for the Blue Demons in the second half during a stretch where Villanova had turnovers on four straight possessions and DePaul looked like it might cruise from there.
Villanova had other ideas. After all, the Wildcats know something about impressive comeback wins, having rallied from 21 down to stun LSU last month. Of course, every comeback is usually helped by a massive collapse.
Burns hit a 3 for a 57-50 lead with 9:49 left before the Blue Demons completely went cold and went 5:36 without a point. The Blue Demons wouldn't score again until Burns hit a jumper with 4:13 to go that made it 65-59.
The Blue Demons had Villanova's number of late, beating them here last January. That was the last time the Wildcats lost at home and they have won 13 straight at the Pavilion since.
The Blue Demons entered hitting only 34 percent of their 3-pointers and hit only nine in their upset win over the Wildcats two weeks ago.
DePaul matched that total in the first half and led by as many as 16 points thanks to making eight of its first 11 3-point attempts. Burns jump-started the streak when he made three of his first four attempts. Tucker hit three straight in one stretch, including one right in front of Wildcats coach Jay Wright, that made it 34-18.
Villanova showed signs of snapping out its funk with an 11-4 run that cut the gap to 40-31 at halftime.
