James had 30 points, 10 rebounds and eight assists while Wade put up 28 points as Miami took command of the best of seven series with the club's third-biggest winning margin in a post-season game.
The build-up to the game had featured plenty of tough talking from the Pacers, in particular from forward Danny Granger, but just as in game three, Miami showed they are at their best when provoked.
Nonetheless the league is likely to be looking at several incidents in the game particularly flagrant fouls from the Heat's Udonis Haslem and a late elbow from team-mate Dexter Pittman on Lance Stephenson.
It was a physical battle at times but the rough and tumble never knocked the Heat off their stride - they outscored the Pacers 22-2 in fastbreak points, the high-flying Wade and James delivering on the bulk of those.
Miami led 49-40 at halftime, ending the half with two emphatic baskets from James - a sign of things to come in a one-sided second half.
Key man Granger had to hobble out of the game just after halftime with a sprained ankle sustained late in the second quarter, and without him Indiana were unable to cope with an inspired James.
In one stunning play, as Miami ran away with the game in the third quarter, James took a long pass from Mario Chalmers one-handed and, falling backwards, lobbed a pinpoint cross-court pass for Wade to dunk.
Miami were fast and direct in transition and there was never a hint of a repeat of the Pacers' Game Three road win which had raised questions over whether the Heat could advance without the injured Chris Bosh.
The league's Most Valuable Player James, whose 40 points in Sunday's win restored Miami's home advantage, was able to take some rest at the start and end of the fourth quarter.
Miami's supporting cast have taken some crticism but forward Shane Battier set the tone with a trio of early three-point shots and he ended with 13 points while Haslem chimed in with 10 points and six rebounds.
The Heat can secure their place in the final against the Boston Celtics or the Philadelphia 76ers with a win in Indianapolis on Thursday.
Despite Tuesday's overwhelming 32-point win, Heat coach Erik Spoelstra is sure his team will face a sterner test back on the road.
"It was a good win. I don't think the score is indicative of anything really. Our challenge right now is to leave it behind us," he said.
"We have to focus on the next one and really commit to keeping this edge that we've had the last two games, knowing that we'll be going into a hostile environment."
Pacer's head coach Frank Vogel was also keen to move on.
"They kicked our butts but, as we've said before, you don't get two wins for a blowout. It only counts once".
As well as Granger's ankle problem, the Pacers will also be hoping that forward David West recovers from a knee injury that restricted his minutes in the second half.