"We were able to get a lot of different contributions (from James)," Heat coach Erik Spoelstra told reporters.
"He had 13 assists, but a lot of defensive plays and the rebounds in traffic really got us out in the open court in the first half."
Having lost to the Atlanta Hawks two days earlier to end their undefeated start, Miami quickly returned to business as usual.
They buried Indiana with a 33-12 second quarter run sparked by James Jones, who caught fire with a trio of three-pointers in quick succession and finished with 14 points after starting in place of Wade.
Chris Bosh added 22 for the Heat, who continued to pad out their lead and were never threatened by the visitors.
"We just really wanted to focus and play the same game we've been playing, and not slow down because (Wade's) out," Bosh said.
"We wanted to do a better job defensively. It's about time for us to start sticking more to our principles and holding each other accountable."
The Pacers moved within 77-65 late in the third but Miami closed the quarter on an 11-1 run and outscored the visitors 30-17 in the fourth for the final margin.
Roy Hibbert led the way with 16 points and 12 rebounds for the Pacers (4-2) who managed just 34 percent shooting as they fell to their second loss in three games.
Danny Granger made just 2-of-13 shots to continue his shooting slump. Indiana's leading scorer last season with more than 20 points per game, Granger entered the night shooting 36 percent from the field this season.