Avery Dingman scored 16 points off the bench for Creighton (13-2, 3-0 Big East), who won their eighth consecutive game and extended the DePaul (8-8, 0-3) losing streak to three.
Creighton's's Ethan Wragge scored 12 points, all of which came from beyond the 3-point line. The Blue Jays shot 56 percent from the field in the second half, including 6-of-10 from 3-point range.
DePaul was led by Brandon Young's 24 points. Cleveland Melvin scored 16.
Creighton led 37-32 at halftime but took control in the second half.