The 22-year-old bagged his biggest career title and, with the US Open starting in one week, he is projected to jump from 21st in the world rankings to a career-high 11th.
Fils swept through the opening set, dropping just three points behind his serve. Tiafoe turned the tables as Fils's errors mounted in the second, but after receiving treatment before the third set, Tiafoe was no match for the surging Frenchman in the third.
"That was my dad on the phone, now I need to call my mom," the delighted winner said at the trophy ceremony, lamenting only that his father missed one of his tournaments for the first time this year.
"Wow, that feels good, that feels good," Fils said. "It's a lot of training, a lot of things, a lot of sacrifice.
"Injury," added Fils, who missed much of 2025 with a back injury and months this year with a hip ailment. "To be able to win one title like this means a lot to me."
He saved two match points in the final game, but Fils set up another with a lob and was able to celebrate as Tiafoe sent a forehand over the baseline to end it after 98 minutes.
Fils blazed through the opening games, breaking Tiafoe on the way to a 3-0 lead and dropping just one point in the first three games.
He dictated the rallies from the baseline, and even as Tiafoe began to find his range, the American was unable to apply any pressure on Fils's serve, Fils finishing off the opening set in 29 minutes with his eighth ace.
Fils suffered his first setback in the second set, saving three break points in the second game but firing a forehand long on a fourth as Tiafoe roared to a 3-0 lead.
The American grabbed all of his chances to level the match after just 54 minutes, but he then called for the trainer for a massage on his right hip, which has bothered him in recent weeks.
Fils regrouped to dominate again, breaking Tiafoe twice for a 4-0 lead in a storming finish.
The result marked the second time that Tiafoe has lost a final in Cincinnati. He fell to Jannik Sinner in 2024.
"I started the first set very, very strong," Fils said. "In the second set I lost a bit of focus; he put me under pressure.
"But I had a small talk with myself in front of the mirror after the second set. I said, 'If you are going to lose, it cannot get worse than this. You need to fight.
"I don't have any words to describe this win," added Fils, who admitted that the injuries slowed his rise. "There is a bit of relief.
"It was a hell of a week. We made a hell of a job, and it is not done yet."