The win, the Cardinals fourth straight, puts Louisville (20-8, 10-4) at 10-4 in the Big East and in solid position for a top four league finish heading into Sunday's matchup on the road against Connecticut.
Even though Louisville shot 49 percent, it was the Cardinals suffocating defense that doomed the Red Storm. The Cards' defense limited St. John's to just 26 percent shooting (15-57), forced 16 turnovers and blocked eight shots.
"We played great defense tonight," Rick Pitino said. "All the guys played a great game and they played great defense. Early on we were playing great defense, we were just giving up second shots."
St. John's took an early 12-8 lead, primarily by hitting the offensive boards, but a 6-0 spurt keyed by two steals helped Louisville take command of the game. The Cardinals closed the first half on a 22-5 run, taking a 36-20 lead to the break.
"Give Louisville and Coach Pitino credit, we didn't play well," St. John's Norm Roberts said. "We played decently in the first ten minutes, (but) hey did a good job guarding us inside."
Louisville dominated St. John's inside, out-scoring the Red Storm 40-12 in the paint. The Cardinals also held their own on the boards, only getting out-rebounded by one, 39-38.
Anthony Mason led St. John's with 19 points.
Louisville travels to Storrs, CT, to face UConn Sunday at noon.