Fitzpatrick hit four-iron to 13 feet for birdie to defeat Scottie Scheffler on Hilton Head Island on Sunday (Monday AEST).
World No.1 Scheffler, trailing by three shots with four holes to play, forced a playoff with a pair of late birdies for a four-under 67 and some help from Fitzpatrick, who hit a poor chip and missed a 20-foot par putt for his only bogey of the day and a 70.
The large gallery watching at the 18th green in regulation filled the Calibogue Sound with chants of "U-S-A!" They returned for the playoff to see Fitzpatrick hit four-iron into a stiff breeze to a pin just over the bunker.
Scheffler followed with his worst swing of the day, a six-iron he fanned so badly that it came up 37 yards short of the hole.
He hit a superb pitch to eight feet, but never had to putt after Fitzpatrick made the winning putt.
Fitzpatrick's reaction was muted, lightly touching his finger to his right ear in a friendly response to the crowd. He knew what he was up against, having gone through a similar atmosphere when Cameron Young beat him at The Players Championship.
The playoff was almost a repeat from when Fitzpatrick defeated another American favourite, Jordan Spieth, in a playoff at the RBC Heritage three years ago. That time, he hit a nine-iron that rolled out to a few inches for the winning birdie.
Fitzpatrick's family used to take holidays to Hilton Head Island when he was a boy. He came to the tournament and thought it would be cool to win it one day, and now he's done it twice.
"It means the world," Fitzpatrick said. "This is a tournament I wanted to win growing up more than any of the majors before I understood more about the game. To go toe-to-toe with Scottie and get it over the line is special."
It was the second straight runner-up finish for Scheffler, who came from 12 shots behind going into the weekend to finish one back of Rory McIlroy at the Masters.
Fitzpatrick won for the second time in the past month. After his runner-up finish at The Players, he won the Valspar Championship.
Sunday's victory, his fourth on the PGA Tour and 13th worldwide, moves him to a career-high No.3 in the world.
South Korea's Si Woo Kim closed with a 68 to finish third.
Karl Vilips was the leading Australian, tied for 33rd place at seven under after a one-under 70 in the final round.
Jason Day had his best round of the tournament, closing with a brilliant seven-under 64 to finish tied for 42nd at six under.
Min Woo Lee was three shots further back in a tie for 60th after closing with a three-over 74.
