The victory was the third straight for the Cardinals (18-9, 9-5 Big East), who opened the week with a 66-60 upset of No. 5 Syracuse. The loss was the eighth straight for DePaul (8-18, 1-13).
Mac Koshwal paced the Blue Demons with a game-high 26 points, tying a career high. He added 10 rebounds.
A large contingent of Louisville fans -- about half the house -- watched the Cardinals use an 11-2 run late in the second half to turn a 49-48 deficit into a 59-50 lead with 3:05 to play.
The Cardinals led 32-27 after a first half that included four lead changes, the last with 6:35 left when Kyle Kuric hit a 3-pointer for a 22-21 Louisville edge. Kuric had seven first-half points and Samuels 12.