SMU (11-4, 1-2 American Athletic Conference) shot just 37 percent (24 of 65) and was plagued by foul trouble from the start. Leading the conference in shooting at 50 percent entering Sunday, it was the first time SMU was held below 40 percent this season.
The Cardinals, coached by Rick Pitino, forced 16 turnovers, 10 in the first half.
"They always play hard under Rick but I thought their energy was great," said SMU coach Larry Brown. "But I also thought we took some terrible shots, especially the first half.
Brown compared Sunday with previous losses at Arkansas and Cincinnati, when his team was pushed into quick shots that negated the chance to draw fouls or get in position for rebounds or transition defense.
"They play their way better than we play their way," Brown said. "I thought that was the key the whole game."
SMU's poor shooting also helped set up Louisville's offense.
The Cardinals hit 25 of 53 from the field (47 percent), the best an opponent has shot against the Mustangs this season. Their 3-point accuracy was especially critical in a game in which SMU controlled the inside 34-28, points off turnovers (16-13), second-chance points (18-3) and bench scoring (24-8).
The Mustangs trailed by as many as 17 points late in the first half and 37-25 at halftime, but rallied within 42-40 with less than 15 minutes remaining.
They trailed 55-51 when Shawn Williams picked up a loose ball and scored in the lane with 5:43 left and were again down by four in the final minute, but couldn't beat their second straight ranked opponent following a Jan. 4 upset over then-No. 17 Connecticut.
Markus Kennedy had 12 points and eight rebounds in his first start of the season for SMU while Williams added 10 points.
Leading scorer Nic Moore had just five points while battling foul trouble and an Achilles injury.
"Our team doesn't believe in moral victories," said Williams, who picked up two fouls in the first 39 seconds. "We lost today. Even though we won when we played UConn, that game is over with. We should have come here with a better focus for this game and we didn't."
Luke Hancock's career-high 23 points, including two free throws with 46 seconds remaining, helped the Cardinals (14-3, 3-1) in Pitino's first collegiate matchup against Brown.
Russ Smith scored 23 points and Montrezl Harrell added 12 points and 13 rebounds as Louisville bounced back from Thursday's loss to No. 24 Memphis despite being outrebounded 48-35, including 20-6 on the offensive end.
SMU made just 13 of 25 free throws and was only 2 of 11 from beyond the arc.
The biggest attraction was the first-ever collegiate meeting between Hall of Famers Pitino and Brown, who brought 2,554 combined victories and three NCAA titles into the contest. Sunday marked the third of eight scheduled matchups nationwide between Naismith Memorial Hall of Fame members, and these two will meet again on March 5 when the Cardinals face the Mustangs in Dallas.
Pitino, who just entered the Hall in September, made a point of heading down the sideline to greet Brown, 73, as they exchanged pleasantries. From there it was all business between two schools fighting to contend in the AAC.
SMU also entered without 6-foot-11 center Yanick Moreira, out 2 to 3 weeks after spraining his right medial collateral ligament on Friday. Brown started the 6-9 Kennedy for the first time in his place.