The Cardinals (21-6, 9-5 Big East) were down by 10 points at halftime but rallied to tie the game in the second half and then outscored DePaul (11-15, 2-12) 13-5 in the overtime period.
Russ Smith and Chris Smith both scored 18 for Louisville. Chris Smith scored the last five points for the Cardinals in overtime.
Brandon Young led the Blue Demons with a season-high 27 points, but it was not enough to prevent their 11th loss in their last dozen games.
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