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-best37.9 points per game.
Meanwhile on Wednesday, the Rockets were withoutClint Capela, who has a virus. Tyson Chandler started in his place and had one point and one rebound in eight minutes.
Adebayo, Butler protect home court vs. Hornets
Bam Adebayo scores 21 points and grabs 13 rebounds, while Jimmy Butler also has 21 points to ensure the Heat remain unbeaten at home.