Fils overcame a second-set blip to steamroll his opponent in the final set to win 6-3 1-6 6-0 on Sunday (Monday AEST).
It was the first time two Black players have met in an ATP Masters 1000 final.
Fils is the third Black man to win a Masters 1000 title, joining American Ben Shelton, who won twice in Canada, and Frenchman Jo-Wilfried Tsonga, who won in Paris in 2008 and Canada in 2014.
It was the second time Tiafoe has appeared in the Cincinnati Open final, losing to Jannik Sinner in 2024.
Fils, who had beaten Australia's No.1 Alex de Minaur in straight sets in the round of 16, overpowered Tiafoe early in the first set on Sunday, winning 12 of 13 points to take a 3-0 lead.
Tiafoe was dominant in the second, rolling to a 3-0 lead.
The American used the time break before the third set to stretch and receive massage treatment on his upper left leg and lower back.
Tiafoe saved two match points in the final game before Fils closed out the victory.
The Frenchman had 11 aces and won 71 per cent of his points on first serve.
He improved to 10-0 in deciding sets this year and 8-0 against American opponents.
Fils won his only previous meeting with Tiafoe in Miami last year, also in three sets.
The 22-year-old is the youngest French champion in Masters 1000 history.
Fils became the second French player to win a Cincinnati final, joining Guy Forget, who triumphed at the 1991 tournament.
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