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.
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Maryland point guard Melo Trimble, considered a lock to leave the program before struggling in the second half last season, has withdrawn from the NBA draft and will return for his junior season.
Louisville's Chinanu Onuaku, who recently underwent a medical procedure to correct a heart rhythm issue detected during the combine, will keep his name in the NBA draft pool.
Andrew White III will return to the Nebraska men's basketball team next season after removing his name from the NBA draft.