Monday night's win brings Louisville its first NCAA men's basketball championship since 1986.
Coach Rick Pitino added this title to the one he won at Kentucky in 1996 and is the first coach to win a championship at two schools. Earlier in the day, Pitino was elected to the Naismith Memorial Hall of Fame.
Michigan was in the final for the first time since the Fab Five led the Wolverines there in 1993.
But the celebration belonged to the Cardinals, who added this to a Sugar Bowl victory this year and also have their women's team in Tuesday's national final against Connecticut.
The Cardinals came in having won six games this season after trailing by 10 or more, including Saturday night's semifinals, when they beat Wichita State 72-68 after also falling behind by 12.
It was a scintillating final act of a season that has been more of a grind, with scoring at its lowest (67.49 points per team) since 1951-52 and shooting at its worst (43.3 percent) since 1964-65.
The 131.2-points-per-game average during March Madness is the lowest since the 3-point line was brought to the game in 1987, though the teams had surpassed that with 5:30 left.
Sitting on the bench with the Cardinals was sophomore guard Kevin Ware, the team's inspiration since snapping his tibia in the regional final last weekend.
The Associated Press contributed to this report.