The third seed came from behind to down the world number one Serbian in four sets, 6-7, 6-4, 7-5, 6-3.

It means that the 31-year-old has now won three grand slam titles and the only one which eludes him is Wimbledon after earlier successes at the Australian Open and French Open.

Djokovic, who was looking for a 13th major crown and a third at Flushing Meadows, looked strong at the outset but failed to take a string of break point opportunities as Wawrinka came to the fore.

The 29-year-old came into the final after three opponents retired earlier in the tournament, but any freshness that might have given him was not enough to see off an inspired Wawrinka.

"This is amazing, for sure, an amazing two weeks," said the Swiss, who missed last month's Rio Olympics.

"I spend so much time on the court. 

"Today I knew it would be a really tough battle again playing the number one player, Novak Djokovic, who always pushes you to play your best tennis if you want to beat him. 

"It was not only in the tennis side but physically and mentally it was really tough, again.

"Honestly after the match I was completely empty."

Djokovic said that he lost his nerve in the "important moments".

"He [Wawrinka] kept his cool, I think that's what decided the match," he said. 

"I guess sometimes it happens, even though you have the experience and know what to do. 

"Just the heat of the moment and importance of the match, I guess, you know, was too strong for me at certain periods of the match. 

"Just if you lose your cool, the match can go away."

In the women's doubles final there was home American success as Bethanie Mattek-Sands and her Czech partner Lucie Safarova downed French duo Caroline Garcia and Kristina Mladenovic 2-6, 7-6, 6-4.

The mixed doubles title went to Germany's Laura Siegemund and Mate Pavic, who disappointed home pairing Coco Vandeweghe and Rajeev Ram 6-4, 6-4.