The Cardinals jumped on the Blue Demons from the opening tip, building an early 19-5 lead eight minutes into the game. Louisville led 37-21 after Juan Palacios scored on a layup with 3:15 left before halftime.
But the Blue Demons ended the half on a 10-2 run to cut Louisville's margin to 39-31 at the half.
Whatever Rick Pitino told his team at intermission worked. The Cardinals came out of the locker room and buried DePaul with a 22-5 run in the first five minutes of the second half to open a dominating 59-36 lead.
Louisville hit 15 of their first 16 second half shots and applied relentless full court pressure that frustrated the Blue Demons into several critical turnovers.
"I think our press got to them," Pitino said.
Terrence Williams led UofL with 22 points and 8 rebounds. Williams his 9-12 shots, including 2-4 three-pointers.
While Williams had a big night for Louisville, the Cardinals attacked the Blue Demons inside the paint the entire game. David Padgett added 20 points for the Cardinals, while Juan Palacios had nine points and six rebounds.
"We wanted to work inside to those guys because we thought those guys could score," Pitino said.
The Cards also got another solid performance from guard Preston Knowles off the bench. Knowles hit 4-of-5 shots, scored 9 points and dished out three assists. Knowles also had a pair of rebounds and a steal in 14 minutes.
Louisville, which won its 4th straight game, continued to play excellent defense against DePaul. The Cards held DePaul to 36 percent shooting, forced 16 turnovers (10 steals) and blocked three shots.
DePaul, meanwhile, couldn't come up with anything to stop the Cardinals. Louisville made 36-62 shots for 58 percent. The Cards also connected on 7-16 three's.
Dar Tucker led DePaul with 22 points. Mac Koshwal led the Blue Demons with 15 rebounds and also scored eight points.
Louisville's next game is at Providence Saturday afternoon.