Louisville stayed within a game of Georgetown for the Big East Conference lead by handing the Blue Demons their 12th loss in 13 games. Georgetown remained on top of the league race earlier in the evening with a thrilling overtime win over Connecticut.
DePaul was within eight points with 7:30 to play, but Louisville went on a 10-point run to clinch the victory.
Peyton Siva added 16 points for the Cardinals (23-5, 11-4 Big East). The teams combined for 37 turnovers, but Louisville eventually won its fourth in a row.
Brandon Young scored 22 points for DePaul (11-17, 2-13).
The Blue Demons have lost 41 straight contests against ranked opponents.