James Jones made his sixth start of the season in Wade's place.
Coach Erik Spoelstra said before Wednesady's game that Wade is day to day and still limping after injuring his right thigh in Sunday's game against the New Jersey Nets. Wade did not participate in the Heat's morning shootaround on Wednesday.
"He is still very sore," Spoelstra said. "We want to make sure he is as healthy as can be down the stretch and for the playoffs. This is a collective decision."
Wade left Sunday's game in the first half but returned after halftime to start the third quarter. He finished with 18 points, five assists, and three rebounds in 28 minutes of playing time.
The Heat (54-23) have five games remaining on the season and are tied for the Eastern Conference's No. 2 seed with the Boston Celtics.
Spoelstra said he weighed playoff implications, but decided rest would be the best option.
"[Wade] understands this time of year," Spoelstra said. "We are playing for something. Everybody in the locker room knows it, but we also have the big picture in mind."
Wade received treatment on Monday. However, at a promotional event for his Jordan brand shoe, Wade said pain was lingering in his leg.
Wade has missed four games this season and is averaging 25.7 points, 6.5 rebounds, 4.5 assists and has registered a player efficiency rating (PER) of 25.6.
Tom Haberstroh is a writer for ESPN Insider.