Kyle Kuric added 15 points and Gorgui Dieng added 12 for the Cardinals (13-2, 1-1 Big East), who lost to Georgetown and Kentucky last week to drop from fourth to No. 11 in the Top 25.
Louisville came into the game second in the Big East in field goal percentage defense at 36.6 percent. The Red Storm never came near that figure.
The Red Storm missed 25 of 26 shots at one point in the first half and were 5 of 35 (14.3 percent) in falling behind 29-18. They finished 18 of 64 for the game (28.1 percent).
It wasn't as if the Cardinals were lighting up the place shooting 43.3 percent (26 of 60) for the game.
D'Angelo Harrison had 24 points for St. John's (7-7, 1-2) and fellow freshman Moe Harkless scored 12.
Louisville trailed 13-12 when it went on a 16-2 run during which St. John's missed all 11 shots from the field and committed three turnovers. Seven players scored the points for the Cardinals in the run.
St. John's never got closer than 12 points in the second half and the Cardinals led by as many as 26 points.
St. John's, which entered the game last in the conference in 3-point shooting at 26.0 percent, finished 2 for 16 from beyond the arc. The Cardinals, 14th in the Big East at 31.4 percent on 3s, were 9 of 22 for the game.
This was the ninth straight game St. John's coach Steve Lavin has missed as he continues to recover from prostate cancer surgery on Oct. 6. Lavin attended the morning shoot-around and watched the game from an upstairs suite. He was on the bench for four games this season with the Red Storm going 2-2.
Louisville has won six of the last seven meetings between the teams and it leads the all-time series 10-4.