The American, 32, claimed his first title since February 2008, finishing at 14 under at the Quail Hollow Club in Charlotte.
Holmes (71) managed to hold off fellow American Jim Furyk, who produced a stunning seven-under 65 in the final round.
Martin Flores (72) ended up at 12 under, a shot ahead of American Jason Bohn (70) and two clear of Englishman Justin Rose (71).
The win is a remarkable achievement for Holmes, who had brain surgery twice in 2011.
He returned in 2012 before breaking his left ankle in March 2013, while he had left elbow surgery the same year.
Holmes was without a top-three finish since 2010 but that changed in perfect fashion as he claimed the title in North Carolina.
He went through the front nine even par after a bogey at the second and birdie at the eighth.
Holmes managed back-to-back birdies at 10 and 11 and another at 15, and that was enough despite bogeys at 16 and 18, where he made a four-foot putt to win.
Furyk's round included five birdies and an eagle, which came at the par-five 15th.
Zimbabwean Brendon de Jonge (69) and American Kevin Kisner (73) were tied for sixth at nine under.
A shot behind were Northern Irishman Rory McIlroy (70), American Roberto Castro (70) and South African Rory Sabbatini (67).
Fresh from his nine-under 63, Phil Mickelson shot a 76 to finish at seven under and in a tie for 11th.