Smith overcame his stomach illness, and a rough first half, by hitting all six of his 3-point attempts after halftime as the 11th-ranked Cardinals rallied from a big early deficit to become the first opponent to win in SMU's renovated home. They beat the 18th-ranked Mustangs 84-71.
''He just came through in a big way,'' Louisville coach Rick Pitino said. ''That was a Michael Jordan-type performance in terms of being sick and gutting it out.''
Smith scored 22 of his 26 points after halftime. He hit three straight 3s right after his alley-oop pass on the go-ahead dunk by Montrezl Harrell midway through the second half for the American Athletic Conference-leading and defending national champion Cardinals (25-5, 14-3 AAC).
After making only one of his five shots before halftime, none from 3-point range, Smith took six 3-point attempts after halftime. He made them all, including those 3 in a 72-second span after the go-ahead dunk and later on consecutive possessions with defenders in his face.
Just because he was making all those shots didn't mean he was suddenly feeling better physically.
''That was crazy. It was happening right when we were in the huddle. You know you get that nasty little belch and then after that I just had to excuse myself,'' Smith said. ''I was trying to play through it. But I realized we had a pretty decent lead so I didn't want to force the issue to make things worse.''
Pitino won the matchup of Hall of Fame coaches, as SMU and Larry Brown lost for the first time in 10 games since moving back into their campus home in January.
The Mustangs (23-7, 12-5), with a raucous sellout crowd for their first home game since 1985 matching ranked teams, jumped out to an 18-5 lead. They were up by 14 points before a miserable closing stretch in the first half.
''You can see why they're a championship team. They started off poorly, and we might have played at an unbelievably high level early,'' Brown said. ''We weren't prepared the way they were, didn't handle the press, didn't handle their intensity at all.''
SMU had already defeated three Top 25 teams at home this season, with decisive wins over UConn, Memphis and Cincinnati.
The Mustangs couldn't add to that list against the Cardinals, who had four players score in double figures.
Chris Jones added 21 points, while Harrell had 19 and Luke Hancock 15. Louisville is guaranteed at least a share of the first AAC title with a victory at home Saturday against No. 19 UConn. No. 15 Cincinnati (24-5, 13-3) has two games left, at home Thursday against No. 20 Memphis before going to Rutgers on Saturday.
Nick Russell had a season-high 18 points in his final home game for SMU. Markus Kennedy had 14 points and Sterling Brown added 10.
The Cardinals never trailed again after Jones scored six points in a matter of seconds.
Jones hit a tying 3-pointer from the left wing with 16:22 left, and immediately dropped back to defend SMU guard Nic Moore. Jones stole the inbounds pass, and made a layup while being fouled by Moore before hitting the free throw for a 40-37 lead.
SMU got even at 41 after Russell got a bounce pass from Markus and made a layup despite being fouled by Harrell.
Russell missed the free throw and Harrell quickly made amends with that rebound, and then a reverse slam on the pass from Smith before a barrage of long-range shots.
SMU led 26-12 when Kennedy made a jumper with 7:04 left, but the Mustangs didn't make another field goal before halftime.
The Mustangs had nine turnovers during that span, four by Russell. And they missed their only three shots.
Jones hit two 3s when Louisville scored 15 consecutive points over a 2 1/2-minute span, his second long-range shot in that span putting the Cardinals up for the first time at 27-26. He had a steal before halftime that he converted into a breakaway layup.
It was the sixth consecutive sellout, and seventh overall this season for the Mustangs. The crowd included Hall of Fame and three-time Super Bowl champion quarterback Troy Aikman, current Dallas Cowboys quarterback Tony Romo and former President George W. Bush, who lives in the neighborhood and whose presidential library is adjacent to Moody.
SMU, seemingly a good bet for its first NCAA tournament berth since 1993, finishes the regular season Saturday at Memphis.
''We've just got to keep it moving. We've been playing great basketball all season,'' Russell said. ''Nothing has changed. We just let this one slip away.''