Wade and LeBron James combined to score 66 points in the showdown between the defending NBA champions and a traditionally powerful Lakers team that is struggling to earn a playoff spot.
Miami led by nine early in the fourth period, but the game was tied on four occasions down the stretch -- the last of the deadlocks coming when the Lakers' Kobe Bryant hit a 3-pointer to make it 90-90 with 2:33 remaining.
The Lakers did not score again, missing three shots from the field and two from the foul line the rest of the way.
After Wade put the Heat in front for good, Ray Allen hit a jumper and James made a shot that banked off the backboard.
James then ended the scoring with a dunk and a free throw with 5 seconds to play.
It was the last stop on a six-game road trip for the Heat, who went 3-3 on the journey. The Lakers, who have lost seven out of nine, will play 10 of their next 13 on the road.
James scored 39 points, grabbed seven rebounds and handed out eight assists. He hit 17-of-25 shots from the field. Wade added 27 points and five rebounds.
Bryant was held to 22 points on 8-of-25 shooting. Metta World Peace added 16 and Dwight Howard had 13.
James, Wade, Bryant and Howard were all named All-Star Game starters earlier in the day.