He carded a six-under-par round of 64 to finish 21 under, one shot ahead of American Ollie Schniederjans.
Former world number one Stenson hit eight birdies in his closing round, including three in a row from the 15th.
Schniederjans also shot 64, while compatriot Webb Simpson finished four shots back in third place.
American Davis Love, at 53 seeking to become the oldest winner in US PGA Tour history, finished eight shots adrift in a tie for 10th.
Stenson, 41, said: "I don't know how many times I'm going to get as close to playing as well as I did at Troon.
"I'm just very pleased with how I closed out this week."
Sweden's Henrik Stenson won the Wyndham Championship to claim his first title since The Open at Royal Troon last year.