Wawrinka broke at 2-1 and then saved three break points himself to extend his advantage to 4-1.
With Djokovic serving at 3-5, Wawrinka whipped a forehand down the line over the high part of the net to earn a pair of set points.
He capitalized on the second attempt when Djokovic’s forehand sailed long, eliciting a roar from the Swiss and a racquet smash from the defending champion.
The third set toggled back and forth, the two men trading breaks to 5-5.
Wawrinka finally seized the advantage in the 12th game, when a Djokovic forehand sailed wide to give the Swiss the break and a two-sets-to-one lead.
With the end in sight, Wawrinka broke again at the start of the fourth set as he raced out to a 3-0 lead against a visibly stunned Djokovic.
Djokovic later received a pair of medical timeouts – at 3-1 and 5-2 – for a right toe injury.
Djokovic kept the championship match alive by holding to make it 5-3, but that was as close as he got to closing the gap.
Wawrinka failed to convert his first match point after Djokovic planted a forehand hit into the net.
But he sealed the deal at the very next attempt when he forced Djokovic into sending a backhand long.
Wawrinka raised both arms in celebration and then made a bee-line to his coaches, family and friends sat at the corner of the court.
“There is no secret,” Wawrinka said. “If you want to beat the No. 1 player in the world, you have to give everything.”
Making his first appearance in the US Open final, 31-year-old Wawrinka moved to a perfect 3-0 in Grand Slam title matches.
He thereby extended his winning streak in finals to 11 matches, dating back to the start of 2014.
He’s now won at three of the four Slams and only needs to win Wimbledon to be the fourth man in history to achieve the career Grand Slam.
Wawrinka saved a match point in his five-set win over Daniel Evans in the third round.
He became the first US Open champion to save a match point en route to the championship since Djokovic did so against Federer in 2011.
The Swiss also became the fifth man in the Open era to win at least two Grand Slam singles titles after turning 30.
And he is the oldest US Open men’s champion since Ken Rosewall, who was almost 36 when he last won in 1970.
For Djokovic, he’ll have to wait until at least January to close the gap on the players above him, namely Rafael Nadal and Pete Sampras, who have 14 titles, and Federer, who has 17.
Djokovic ties Ivan Lenld’s Open era record with five finals losses in New York.