Bryan's four-under effort at Harbour Town in Hilton Head, South Carolina, gave him a 13-under par total of 271.
He became the first South Carolina-born player to win the event since it was launched in 1969.
Bryan also booked his invitation to next year's Masters.
After a dominant season on the developmental Web.com Tour last year, Bryan admitted he had hoped to win on the main tour in time to book a berth in this year's Masters -- which was won by Sergio Garcia last week.
"But I guess the week after Augusta's not too bad," he said.
After a bogey at the third, Bryan strung together four straight birdies before another bogey at the eighth.
After birdies at 13 and 15 he arrived at 17 to realize he was within sight of victory.
"Honestly I wasn't nervous at all all day," he said. "Then at number 17 I got up and I just threw up a little bit in my mouth, and I was like, 'Well, shoot, I guess this is what nervous feels like.'
"But I was able to get it back together," he added.
For England's Donald it was a fifth runner-up finish at Harbour Town.
He got off to a rocky start with a double-bogey seven at the par-five second but had five birdies the rest of the way in his 68 for 272.
Overnight leader Jason Dufner slid down the leaderboard with a five-over 76 that included a double bogey and four bogeys after his only birdie of the day, at the second hole.