Paul George helped the Pacers fight back from a 13-point deficit, scoring 15 of his 17 points in the second half of a contest pitting the teams with the best records in the East.
The Heat won last year's conference finals in seven games.
David West added 17 points and nine rebounds for Indiana, which improved to an NBA-best 19-3.
The Heat, meanwhile, dropped a third in five games as LeBron James was limited to 17 points, 14 rebounds and six assists.
Dwyane Wade added 17 points.