It was the second straight Big East win for DePaul (10-8, 2-3). The last time the Blue Demons won two straight in the league was January 5, 2008.
The game was a see-saw battle that featured 16 times where the score was tied up.
DePaul started to gain some momentum following a Sir'Dominic Pointer's technical foul when he mugged DePaul guard Brandon Young with 13:57 left in the second half.
"I knew we were going to go on a run after that, because I knew we were starting to get in St. John's head," said Young.
St. Johns's (9-7, 0-4) rallied however, but then sputtered down the stretch.
DePaul's Cleveland Melvin put the Demons on top 76-75 with a jumper with 2:19 to go.
St. John's failed to score in the final three minutes of the game.
"We were in a hurry, we rushed, and we missed some shots," said Red Storm coach Steve Lavin.
"I thought our guys did a good job of moving their feet and either turning them over or getting a blocked shot," DePaul coach Oliver Purnell said of his team's defense.
While St. John's was rattled, DePaul played patient and poised in the final two minutes.
"Our execution was better," Purnell said. "We're getting higher percentage shots."
D'Angelo Harrison led all scorers and the Red Storm with 24 points after being questionable with a mild concussion that occurred in Saturday's loss to Villanova.
Freshman guard Rysheed Jordan added 16 points and Orlando Sanchez contributed with 11 points for St. John's.
DePaul freshman Billy Garrett Jr. led the Blue Demons with 21 points and five assists, while his backcourt mate Brandon Young scored 19 points and have five assists.
"I thought our guards were outstanding," Purnell said of Garrett and Young. "That's an example of guards winning for you."
"Our chemistry is getting a lot better," Garrett said of his play with Young. " I know where he's going to be, he knows where I'm going to be."
Four Blue Demons reached double-figures. Melvin added 16 points and seven rebounds, while Tommy Hamilton IV chipped in with 13 points.
The Blue Demons now travel to Philadelphia where they will meet Villanova on Saturday afternoon.
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