The Heat coach also lost a former All-Star guard. Ray Allen, the NBA's career record-holder for 3-pointers was out with the flu.
Wade has missed 19 games this season, mostly by design. Team officials wanted him to rest his sore knees so he could kick things into high gear for the playoffs. But Monday's absence was not part of the plan. After the team initially said the All-Star guard hurt his ankle. The Heat are now calling it a strained left Achilles tendon.
Spoelstra waited until after warmups before activating Wade for one of the season's most highly anticipated NBA games.
Wade scored a season-high 32 points in Miami's win over the Pacers on Dec. 18 and is averaging 19.3 points.
Wade practiced Tuesday and participated in Wednesday morning's shootaround, then sat on the bleachers with ice wrapped around both of his problematic knees.
"It's something I can play with. I took a few days off to rest it and I'm ready to go tonight," Wade said.
With Wade back, it appeared the Heat (48-21) would be at full strength for Round 3 of this increasingly heated rivalry - until Allen came down with the flu.
Spoelstra spent most of the afternoon contemplating how to adjust without Allen coming off the bench.
"It will probably be by committee. Everybody's ready to go, there's no excuses and we have more than enough to get the job done," Spoelstra said.
The only medical concerns for Indiana are backup center Andrew Bynum, who is out indefinitely with soreness and swelling in his right knee, and backup point guard C.J. Watson, who is out with a strained right hamstring.
All this only adds to the intrigue of one of the league's most intense matchups - on and off the court.
The Pacers won the first meeting 90-84 in Indianapolis on Dec. 10. Eight days later, the Heat rallied late for a 97-94 home victory. The teams will meet one more time, April 11 at Miami, before attention turns to what many expect to be a rematch in the Eastern Conference finals.
At times, the Heat have been perturbed by Indiana's bold talk about earning the No. 1 seed in the East, though All-Star forward Chris Bosh acknowledged Wednesday that he "missed" playing the Pacers.
"You want to keep your friends closer and your enemies closer," he said. "We know what is for in the East and they know what it is for, and we both know that where we want to go, we have to play each other."
The last time these teams met in Indy, Miami also took exception to the Pacers' description of it as a "championship game."
But Indiana doesn't understand the fuss.
When asked whether publicly promoting the goal of finishing No. 1 in the Eastern Conference was a good move, All-Star swingman Paul George said: "I think it's a great move. I don't know why we get criticized for, you know, having a goal. I don't know if that wasn't popular back in the day. But we was just a team that set out a goal for ourselves and a goal we felt was very achievable."
Indiana (51-20) has held that No. 1 spot all season, though Miami is now within striking distance.
With a win at Indiana, the Heat would get even with Indiana in the loss column and move within one game of the Pacers.
Neither team has played particularly well lately. The Pacers have struggled offensively, the Heat defensively, and both have gone 7-7 in March.
Last weekend, Bosh challenged his teammates to play with more passion.
Now George is encouraging his teammates to share the ball more and have more fun, especially with so much at stake.
"We got a lot of guys looking to make plays one-on-one, which is not us. We're used to playing as a team, playing as one, and we lost that. I don't know where it went, but we lost it along the way," George said. "So we can use a game like tonight to try to get back on track."