Shrugging off a three-hour rain delay and the overwhelming hostility of the Arthur Ashe Stadium crowd, the 28-year-old world number one captured his second title in New York to add to his 2011 triumph.
The defeat shattered 34-year-old Federer's bid to become the oldest US Open champion in 45 years and left him marooned on 17 Grand Slam titles, the last of which came at Wimbledon in 2012.
Djokovic added the US Open title to his Australian Open and Wimbledon victories this year.
Had it not been for a heartbreaking loss to Stan Wawrinka in the French Open final in June, the rock-solid Serb would have been celebrating a rare calendar Grand Slam.
Djokovic's 10 majors takes him level with American Bill Tilden and just one shy of Bjorn Borg and Rod Laver on the all-time list.
Federer was ultimately undone by 54 unforced errors and his ability to convert just four of 23 break points.
"I have tremendous respect for Roger and the challenge he presents," said Djokovic, who is now 21-21 in career meetings with Federer.
"He's the best player ever. I knew I needed to play my best in order to win. It's an incredible evening."
He added, "I love this sport and all these achievements are incentive for me to keep on going."
Federer insisted he would be back to try again in 2016.
"I love tennis. I'll see you back here next year," said the veteran.
"I'm pleased with where my game is, but playing a great champion like Novak is always difficult."
With the likes of Robert Redford, Sean Connery and David Beckham watching, and with Eva Asderaki-Moore making history as the first woman to umpire the men's singles final, Djokovic was dialled in from the start despite heavy rain forcing a three-hour delay and an evening start.
He forced five-time champion Federer, playing in his first US Open final in six years, to save three break points in a six-minute opening game.
The top seed held to love and then broke for 2-1 --- it was just the third time in 84 service games at the tournament that the Swiss veteran had been broken.
However, with the playing surface still damp from the hours of rain, the Serb suffered a worrying fall in the next game, turning over on his right ankle and bloodying his elbow.
Federer pounced to retrieve the break but the Serb was soon back in the ascendancy and Federer was broken again in the seventh game.
Federer saved a set point in the ninth, but conceded the first set with a netted backhand in the 10th game.
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