Heat coach Erik Spoelstra told reporters that Butler, who missed Wednesday morning's shootaround, is "wiped out" and is battling a condition similar to guard Goran Dragic's recent sinus infection.
The Heat officially ruled him out about 90 minutes before tipoff.
Butler is averaging team highs of 18.9 points and 6.7 assists per game.
Butler had 18 points and nine assists earlier this month when the Heat limited Harden to 29 points during a 129-100 blowout win in Miami. Harden is averaging a league-best 37.9 points per game.