Wade also finished with 12 rebounds for the Heat, who bounced back from a loss to Boston on Sunday.
LeBron James scored 10 of his 27 points in the fourth quarter and Chris Bosh added 22 points and eight rebounds for Miami, which has won eight of nine.
Roy Hibbert scored 18 points and Tyler Hansbrough added 16 for the Pacers. Indiana has won seven of nine under interim coach Frank Vogel, with both losses coming against the Heat.
Miami led by 24 points in the first half, then lost the lead before regaining it for good in the fourth quarter.
James threw the ball off the backboard, caught it with one hand and dunked to give Miami a 93-91 lead with six minutes to play. James converted a basket in close over the 7-foot-2 Hibbert, then scored on a tip-in to push Miami's lead to 99-94, and the Heat led the rest of the way.
Wade dominated Mike Dunleavy for 16 points in the first 5:05 of the game. When Vogel finally switched the matchup and brought in rookie Paul George, Wade splashed a jumper in George's face seconds after he entered. Wade finished the period with 22 points, the most he has scored in a quarter this season. One of his baskets was a jumper from behind the backboard.
Miami led 41-19 at the end of the quarter. It was the most points the Heat have scored in a quarter and their highest point differential in a quarter this season.
The Pacers went to their bench and flipped the script. Led by Hansbrough, the Pacers shot 64 percent in the second quarter. Indiana outscored the Heat 35-17 in the period and trailed 58-54 at halftime.
Miami led 64-58 when George made a 3-pointer. Collison stole the inbounds pass, and Danny Granger made a 3-pointer to tie it with 8:33 left in the third quarter. The Pacers took a 73-68 lead when George made three free throws after getting fouled on a 3-pointer with 5:33 left in the third quarter.
Miami regained the lead with a 6-0 run, and the advantage seesawed through the rest of the quarter. Hansbrough hit a mid-range jumper as time expired in the third quarter to give the Pacers an 83-82 lead.
Notes: Miami shot 71 percent in the first quarter and outrebounded the Pacers 15-6. ... Pacers G Brandon Rush returned after missing 10 straight games with a sprained right ankle. ... Miami C Erick Dampier was called for a technical foul with 1:05 left in the 2nd quarter. ... Indiana had its fifth sellout of the season. ... Indiana has scored at least 100 points in every game since Vogel took over.