The 31-year-old Swiss, who defeated Djokovic on his way to winning the 2014 Australian Open and 2015 French Open, denied the world number one a third grand slam title this year following the Serb’s wins in Australia and France.
Wawrinka, who does his best work with titles on the line, set up his championship point with an easy volley after sending a fatigued Djokovic deep into the backhand corner.
A Djokovic backhand that sailed long ended the nearly four-hour slugfest at Arthur Ashe Stadium.
“This is amazing,” Wawrinka said at the trophy ceremony. “I came here without the goal to win it, but every time I step on the court I tried my best to win every match.
“I think I played quite a lot of tennis these two weeks, I am completely empty. I had to bring everything I had today against Novak. It was so much emotion.”
It was another Flushing Meadows disappointment for Djokovic, who in seven trips to the U.S. Open final has twice won the title and finished runner-up five times.
“He is a great champion and deserves to win this title,” the 12-times slam winning Serb said in congratulating Wawrinka.
“We played almost four hours and we both felt it. We both felt the demanding match we played today physically but he came out on top. In the decisive moments he was a better player, he was tougher mentally.”
Djokovic who won the first set tiebreak 7-1 by running off the last five points, saluted Wawrinka as a “big match” player. The Swiss has won three of their seven grand slam encounters.
“He loves to play in the big matches,” Djokovic said. “He comes up with his best game. He’s so solid from both corners. He’s got a good slice and amazing one-handed backhand, all corners. Big serve. Moves well. He’s a very complete player.”
It was a grueling, groundstroke battle that featured captivating rallies and brilliant shot-making from the familiar foes.
Wawrinka trailed Djokovic 19-4 in their career meetings, but the hard-working Swiss saves his best for the big stage and he came through with a superlative performance that extended his remarkable streak to 11 straight wins in tournament finals.
As the match wore on, Wawrinka proved stronger and appeared to have Djokovic on the ropes early in the fourth set, the Serbian breathing heavily after some rallies and clutching at his leg in discomfort after being broken to trail 0-2.
Djokovic was granted a medical timeout after holding serve for 1-3.
Djokovic, who had injury questions entering the slam and benefited from an easy ride that included a walkover and two retirements, took off both shoes and had some toes taped.
The six-minute interruption did little to stem the victory charge by Wawrinka, who built his winning edge by being better on the most important points.
The Swiss led Djokovic by the narrowest of margins, 144 to 143 in total points.
Wawrinka cashed in on six of 10 break point opportunities, and frustrated Djokovic by saving 14 of 17 break points against him to become the oldest U.S. Open winner since Australian Ken Rosewall (35) in 1970.
The victory was worth $3.5 million for Wawrinka, who is only missing a Wimbledon victory to complete the coveted career grand slam.
He is a perfect three-for-three in grand slam finals.