Wade, who had 33 points in the first three quarters, was double-teamed in the final quarter and missed all three of his shots, allowing the Orlando Magic to pull away for an 86-76 victory.
"We didn't want him attacking the basket, but not only scoring that way but getting us in foul trouble and (him) to the line," said Orlando coach Stan Van Gundy, who coached Wade his first two-and-a-half seasons in Miami. "But he shot us right out of that idea and we had to get a lot more aggressive in the second half. That was the plan. It didn't work well, but that was the plan."
Orlando's plan improved in the fourth quarter, when the Magic put rookie Courtney Lee on Wade and sent Lewis at him on double teams. Wade had only one assist and one turnover in the final period as Orlando turned a 67-65 lead into an advantage that grew to as many as 12 points in the closing minutes.
Dwight Howard, who leads the All-Star balloting, added 15 points and 15 rebounds for the Magic, who extended their regular-season winning streak to 10 over their instate rivals.
Wade, the NBA's leading scorer, hit 12 of his first 18 shots before finishing 16-of-29 for the game, with six assists and seven rebounds. He missed his last six field goal attempts.
"They were all doubling," Wade said. "We all knew what Stan was going to do. It's not a secret that after a while they were going to send the guys. He does it every time we play them."
Heat coach Erik Spoelstra said that the Magic's aggressive defense disrupted the Heat's spacing and screens.
"They really kind of jailed us in the fourth quarter," he said.
The Heat made only two of their first 12 shots in the fourth quarter, and backup forward Tony Battie hit a pair of baskets as Orlando turned a two-point lead into a 75-69 advantage with just over six minutes left in the game.
Howard had a putback and free throw with just more than four minutes left to put Orlando ahead to stay, 80-72. The Magic's lead grew to as many as 12 in the final minutes.
Orlando also enjoyed a significant advantage at the free throw line, making 20 of 30 attempts while Miami made nine of 10.
Howard made three of five free throws and at one point late was bear-hugged by Jamaal Magliore when he tried to go up for a layup.
Van Gundy said Howard's done an admirable job masking his frustration with what he considers obvious fouls, but added that he didn't expect anything else from Magliore.
"He's like the guys in hockey who can't skate, but have one role," Van Gundy said. "His role is to beat the hell out of people."
Magliore had already left the Heat locker room before Van Gundy's comments could be relayed to him, but Spoelstra has repeatedly said Magliore's role is that of an enforcer.
Lee, meanwhile, is one his way to earning a burgeoning reputation as a shutdown defender.
The rookie from Western Kentucky held Wade without a point in the final quarter -- but that doesn't mean he's earned pass from his coach.
"I still get (ticked) off at him," Van Gundy said. "If you take the minutes he plays and you put him on a guy like Dwyane Wade, then you don't expect him to make any mistakes. But he's done well."
While Orlando has been nearly unbeatable against Miami, the Magic have taken advantage of Wade's absence. The Heat's best player has appeared in just four games during the losing streak, including two of the last seven meetings between the teams.
The Magic made only three of their first 15 3-pointers, but Lewis hit a pair in the final 65 seconds of the first half to give the Magic a 45-44 lead at the break.
Lee made a 20-foot jumper at the third-quarter buzzer to give Orlando a 67-65 lead.
Hedo Turkoglu made only one of his 14 field goal attempts and finished with seven points for the Magic, who extended their streak of home wins to nine.
"That was sort of a nightmare night," Van Gundy said.
The Heat (17-14) were looking for their sixth win in seven games following Tuesday's 104-95 victory over Cleveland.
Rookie Mario Chalmers and Cook shot a combined 11-of-14 from 3-point range on Tuesday as Miami finished a season-best 61.1 percent from beyond the arc. Chalmers, who hit a season-best six 3s, scored 21 points and matched a season high with eight assists.
Things didn't go nearly as well on Friday night.
Chalmers made only one of seven field goal attempts in the first half, and Cook hit only one of three. They were a combined 3-of-12 from beyond the arc.