DePaul (8-13, 1-7) got off to a shaky start and trailed by as much as 21 points in the first half.
Their problems were further compounded by foul trouble with three starters - Eli Cain, Billy Garrett, and Tre’Darius McCallum all on the bench in the first half with three fouls apiece.
DePaul did manage to rally to come within nine points of No. 16 Creighton (19-3, 6-3) mid-way through the second half, but the Bluejays held on during the game’s final stretch.
While DePaul shot well from beyond the arc (41 percent, they shot just 38 percent overall from the field.
Billy Garrett, Jr. led the way for the Blue Demons with 18 points on six of 10 shooting.
DePaul freshman Brandon Cyrus added 12 points and six rebounds. Eli Cain finished with nine points, but shot just four of 17 in the losing effort.
Chris Harrison-Docks came off the bench to score eight points, but was three of 10 from the floor this afternoon.
Khyri Thomas led the Bluejays to the win with 18 points on seven of 14 shooting.
DePaul returns to Allstate Arena on Tuesday night to host the Georgetown Hoyas.