Mukhtar tallied all three goals in the first 16 minutes.
Mukhtar, who entered with a team-leading four goals, took advantage of breakdowns on Chicago's back end to open the scoring in the 10th minute, and he came through again three minutes later.
Then after Fire captain Johan Kappelhof was shown a red card in the 14th minute for impeding a streaking C.J. Sapong, Mukhtar brilliantly curled in a free kick off the crossbar in the 16th to complete the quickest hat trick to open a match, according MLS, and give Nashville a commanding 3-0 lead.
Mukhtar, who nearly had a fourth that was canceled on an offside call, posted his only other career hat trick as a member of Germany's Under-20 World Cup team in May 2015. This, however, was the first hat trick in the two-season MLS history for Nashville, which is 6-0-5 at home since losing to FC Dallas in November 2020.
Sapong, who assisted on Mukhtar's first goal, scored against his former club in the 39th minute. Nashville, which recorded 12 shots on target, set the club mark for most goals in a game via Brian Anunga's score in the 62nd.
Chicago, which played all but 14 minutes with 10 men after Kappelhof's booking, didn't completely roll over and scored two minutes into the second half through Ignacio Aliseda's left-footer.
The Fire, who entered on a 2-0-1 run, have been outscored 13-2 while losing all five 2021 matches on the road, where they are 0-11-5 since winning at Orlando City on Oct. 6, 2019.
Fire head coach Raphael Wicky was away from the club due to a family medical issue in his native Switzerland. Assistant and former Chicago head coach Frank Klopas guided the team Saturday and will again do so against D.C. United on Wednesday.