Now, the Heat can only hope both superstars won't be on the bench Thursday in Atlanta.
James also grabbed eight rebounds and the Heat turned up the defensive intensity minus their All-Star guard. Wade sat out with a sore left foot, and his status for Thursday's game at Atlanta is uncertain.
Wade, a six-time All-Star, injured his foot in the second quarter at Charlotte on Dec. 28. He missed the first 10 minutes of the third period but played regular minutes the rest of the game and in the two that followed. He skipped Wednesday's shootaround, though.
The Heat had a scare late in the third quarter when James went down underneath the basket with a left ankle injury. He also is questionable for Thursday.
"It's been better, but it feels OK right now," James said. "We'll see how I feel in the morning."
James appeared to step on the foot of Indiana's Paul George while attempting a fast-break layup. After staying on the court for a few seconds James got to his feet, prompting applause from the sellout crowd, and resumed breaking down the Pacers.
Still, the Heat could be without two of their three big stars in Atlanta.
"We will have to see," coach Erik Spoelstra said when asked if James would play Thursday. "He has sprained that same ankle every year, he says at least one time a year."
Indiana, a fashionable pick to be one of the surprise teams in the East, had a miserable second quarter, going 1 for 15 from the field and committing 10 turnovers that Miami turned into 10 points.
"Lack of execution, missed open shots and their defense -- it was a combination of everything," Pacers coach Frank Vogel said. "A perfect storm."
Miami took a 62-39 halftime lead thanks to a 25-6 run to close the second quarter.
Indiana's main problem, however, was that it couldn't slow Miami's transition offense. And because the Pacers shot so poorly and committed so many turnovers, all the Heat had to do was grab the ball and start running, and they did it quite successfully.
The Pacers trailed 29-27 after the first quarter. But in the second half, they never got closer than 12 points and the lead eventually ballooned to 36.
Indiana's Danny Granger scored only six points on 2-for-13 shooting. He missed six of his seven shots in the first half and committed three turnovers.
The Pacers ended up shooting 34.8 percent from the field. They committed 23 turnovers that Miami turned into 28 points.
This was Indiana's biggest test of the season after beating Detroit, Toronto, Cleveland and New Jersey.
Indiana guard Lance Stephenson sprained his left ankle in the second quarter and didn't return. ... Granger hit a 3-pointer and has hit at least one in 22 consecutive games, the longest active streak in the NBA. ... Miami, among the NBA's top defensive teams, didn't take a charge against Indiana. The Heat had been averaging 2.3 charges taken per game.
Jonas Valanciunas slaps in DeMar DeRozan's missed free throw attempt, and it puts the Raptors up two with under two minutes remaining against the Heat.
Former Suns coach Jeff Hornacek and current Hornets assistant coach Stephen Silas will interview for the Houston Rockets' coaching vacancy, sources told ESPN's Brian Windhorst.
Joe Johnson lobs the ball up and Hassan Whiteside does the rest throwing down a two-handed hammer in the second quarter against the Raptors.