Mukhtar gave Nashville (10-3-5) the lead early, scoring unassisted in the 11th minute.
Nicholas Gioacchini scored his seventh goal of the season, unassisted in the 41st minute to pull St. Louis City (9-6-2) even at halftime.
Mukhtar gave Nashville the lead for good in the 70th minute, scoring after St. Louis City defender Kyle Hiebert picked up a second yellow card that left the expansion team a man down.
Mukhtar wrapped up the victory and polished off his hat trick when he took passes from Dax McCarty and Alex Muyl in the 75th minute and scored his league-leading 13th goal of the season. Mukhtar, the reigning MVP, entered play in a four-way tie for first place in the race for the Golden Boot, which Mukhtar won last season.
Mukhtar has had a hand in at least one goal in six straight matches at home (8 goals, 4 assists). He has been involved in 51 goals at home since the start of the 2021 season, 14 more than any other player in the league.
Joe Willis finished with one save for Nashville. Roman Bürki saved two shots for St. Louis City.
Nashville has won all four of its home matches against expansion teams with clean sheets in the first three.
St. Louis City won its first three road matches but has since gone 0-4-1 away from home.
Nashville had a nine-match unbeaten streak in 2021.
St. Louis City returns home to host Real Salt Lake on Wednesday. Nashville travels to play Montreal on Wednesday.