CHARLOTTE, May 5, 2014 (AFP) - Holmes fired a final-round 71 on the par-72 Quail Hollow course for a 14-under total of 274 and a one-stroke victory over Jim Furyk.
Furyk stormed into contention with a seven-under 65, but overnight leader Holmes's effort -- capped by a three-footer for bogey at the last -- was good enough for a third career title.
His previous two came at Phoenix in 2006 and 2008, but since then he'd been slowed by health troubles.
Holmes had surgery late in 2011 to correct structural defects in the cerebellum, the part of the brain that controls balance. He was diagnosed after experiencing vertigo-like symptoms.
Complications required a second surgery and while he made a successful return to the PGA Tour in 2012 Holmes was sidelined again after breaking an ankle rollerblading in March of 2013.
He also had elbow surgery last year, missing much of 2013 before returning at Torrey Pines in January.
He began 2014 playing on a medical exemption, but had won enough money by April to secure his spot on tour for the remainder of the year.
"It feels great," Holmes said. "It's been a long journey for me. I've had some ups and downs, so it's a great feeling to be out here and get one done."
American Martin Flores carded a final-round 72 for sole possession of third place on 276. Jason Bohn carded a 70 for 277.
US Open champion Justin Rose of England carded a 71 for fifth place on 278.
Phil Mickelson, who won the most recent of his five major titles at the British Open last year, had charged into contention on Saturday with a nine-under par 63.
But the US star slumped to a four-over 76 that included three bogeys and one double-bogey to fall into a tie for 11th on 281.
Furyk finished nearly two hours ahead of Holmes, delivering a bogey-free round highlighted by his chip-in for eagle from 62 feet at the par-five 15th.
Furyk then could only watch Holmes' progress from the locker room.
Holmes picked up shots at 10, 11 and 15. After a bogey at 16 he arrived at 18 leading by two.
Holmes fired his tee shot into the trees, barely missed a bunker with his second shot and finally two-putted from 45 feet for a bogey and the win.
"Nobody is real comfortable on those last three holes. You can definitely have some disasters there," Holmes said. "I felt good going all day. I played well and hit the driver good all day. It was a good day for me."
Leading scores after Sunday's final round of the $6.9 million US PGA Wells Fargo Championship (USA unless noted, par-72):
274 - JB Holmes 70-67-66-71
275 - Jim Furyk 72-69-69-65
276 - Martin Flores 67-68-69-72
277 - Jason Bohn 73-67-67-70
278 - Justin Rose (ENG) 69-67-71-71
279 - Brendon de Jonge (ZIM) 80-62-68-69, Kevin Kisner 72-66-68-73
280 - Rory Sabbatini (RSA) 74-68-71-67, Roberto Castro 71-70-69-70, Rory McIlroy (NIR) 69-76-65-70
281 - Kevin Chappell 73-70-70-68, Michael Thompson 71-69-69-72, Phil Mickelson 67-75-63-76
282 - Kevin Streelman 72-69-71-70, Zach Johnson 71-70-69-72, Geoff Ogilvy (AUS) 72-67-70-73, Jonathan Byrd 68-71-70-73
283 - Ryan Moore 70-71-76-66, Gary Woodland 71-72-68-72, Charles Howell 69-71-70-73, Kevin Na 69-72-69-73, Martin Kaymer (GER) 69-69-70-75
284 - Jason Kokrak 75-68-73-68, YE Yang (KOR) 73-72-71-68, Stewart Cink 68-70-74-72, Robert Streb 71-69-71-73, Wes Roach 71-71-69-73, John Merrick 71-70-70-73, Mark Wilson 72-72-66-74