The Heat came back from their lone loss of the season, holding the Pacers to 12 points in the second quarter while piling up a 24-point halftime advantage.
James had 13 assists and grabbed eight rebounds, but gave Miami fans some concern at the end of the third quarter when he stepped on the foot of Indiana's Paul George while heading to a layup. James hit the floor and grabbed his left ankle, but he eventually regained his feet and never left the game.
The Heat suffered their first loss of the campaign Monday against Atlanta.
Roy Hibbert led the Pacers with 16 points and 12 rebounds. Indiana has lost two straight after winning its first three of the season.