Three shots clear of compatriot Kevin Chappell after the third round, Kisner stretched his advantage to six by the turn after five front-nine birdies.
The 31-year-old was never threatened on the back nine as he completed a blemish-free six-under-par 64.
Chappell shot a 67 to take second with Northern Ireland's Graeme McDowell one further back in third after his 67.
McDowell, 36, had been aiming for back-to-back wins after triumphing in Mexico last weekend.
Kisner's victory came after four runner-up positions on the PGA Tour this year.
The South Carolina native was beaten in play-offs at the Heritage event, the Players Championship and the Greenbrier Classic before being pipped by Scotland's Russell Knox at the World Golf Championship Champions event in Shanghai earlier this month.
Kisner, who picked up over £675,000 for his triumph, owns a second home close to the Sea Island course and he made use of his knowledge of the venue by producing a dominant and hugely impressive display.
"I knew one day it was going to happen for me and it did on the front nine when I holed all those putts and I was able to kind of coast in on the back nine," he said.
McDowell performed admirably with his bogey at the 16th, after his approach was plugged in a bunker, his first dropped shot in 46 holes.
Californian Chappell, 29, remains without a PGA Tour victory after his runner-up spot.
American Kevin Kisner won his first PGA Tour title as he earned a six-shot triumph at the RSM Classic in Georgia.