James netted 30 points, grabbed 10 rebounds and dished off eight assists while Wade pumped in 28 points for Miami, which pushed the Pacers to the brink of elimination in their Eastern Conference semifinal series.
The pair combined for 70 points in the Heat's Game 4 victory Sunday, making up for the absence of injured all-star forward Chris Bosh in both games.
Miami connected on a playoff team-record 61 percent of their shots from the floor in the win.
Shane Battier contributed 13 points for the victors.
Indiana got only 10 points from leading scorer Danny Granger before he succumbed to an ankle injury in the third quarter.
The Pacers will try to stay alive when the series shifts back to Indianapolis for Thursday's Game 6.
Notable deaths of 2014 [PHOTOS]