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.
adidas Men's Louisville Cardinals Hardwood Black Basketball T-ShirtPrice: $21.99 Shop
Top-50 prospect Jaylen Nowell committed to Washington on Wednesday. Nowell, a shooting guard, is No. 45 on the ESPN 100.
Mitchell Robinson, the No. 15 player in the country in the Class of 2017, has committed to Western Kentucky.
ESPN College Basketball reporter Myron Medcalf discusses whether Shaquille O'Neal's son Shareef could end up playing at LSU, Kentucky or Michigan State.