Nadal, 27, added the 2013 trophy to his 2010 triumph, when he completed a career Grand Slam, and capped a year that has seen him claim 10 titles and stretch his season record to 60 wins and just three losses.
Monday's win also earned the Majorcan a total of $3.6 million (€2.71 million), which takes his career earnings through the $60 million mark, and also edged him closer to Roger Federer's record of 17 majors and put him one behind Pete Sampras.
In the pair's record-setting 37th meeting, world number two Nadal, who only returned to the tour in February following a seven-month injury layoff, took his lead over Djokovic to 22-15 as he added the US Open crown to the eighth French Open he claimed in June.
"It's very emotional. All my team knows what this means to me," said Nadal, who now has 60 career titles and only returned to the sport in February after a seven-month injury absence.
"Novak always brings my game to the limit. He is an amazing player. He will go down as one of the greatest in the sport."
For Djokovic, playing in a fourth successive final in New York, it was a devastating defeat in a year which started with a fourth Australian Open title but was followed by a semi-final loss at the French Open to Nadal and a Wimbledon final mauling by Andy Murray.
For the neutrals, it was a memorable contest which showcased thrilling athleticism, delicate touch and exhausting, brutal rallies, one of which was fought out over 54 strokes.
Djokovic lost 11 of the last 13 games with his challenge fatally undermined by 53 unforced errors.
"I would have loved to win. But it was obvious that in the important moments he played better tennis, and that's why he deserved to win. I congratulate him, and I move on," said Djokovic.
"I had my momentum from midway second set to the end of the third where I was supposed to use the opportunities that were presented to me, and I didn't do it. I didn't deserve to win."
Nadal, in his 18th major final, was comfortably the more settled player in the opening stages, finding pin-point accuracy while Djokovic was sluggish and heavy-footed.
Nadal, who missed the 2012 tournament, sensed the Serb's uneasiness and broke for a 2-1 lead, mastering the occasion as well as the tricky breeze.
Even the technology was on the Spaniard's side as a successful challenge on triple break point gave him a double break for 5-2.
With a host of show-business glitterati looking on — including Sean Connery, Leonardo DiCaprio, Jessica Alba and Justin Timberlake — Nadal claimed the first set with ease after 42 minutes.
The omens were looking good for the Spaniard, who had only lost three out of 154 career Grand Slam matches when winning the first set.
But 26-year-old Djokovic stormed out of his slumbers and broke for 4-2 in the second set after a 54-shot rally, Nadal dumping an approach into the net.
It was only the second time Nadal had dropped serve in the tournament and the setback fired him into an immediate response, hitting back at 3-4, before Djokovic broke again for 5-3 on a modest 28-shot exchange.
This time, the world number one backed up it up to level the final, taking the 58-minute set with a down the line winner.
Djokovic broke to love in the opening game of the third and had a point for a double break in the third before Nadal clung on to avoid dropping serve for the fourth game in a row.
The world number two then capitalized on a sloppy Djokovic service game to level at 3-3, but the twists and turns became a tumble for Nadal, who slipped to the floor in the ninth game.
Unruffled, he saved three break points to sneak ahead 5-4 and then unleashed a deep forehand which Djokovic could only slap long as Nadal went into a two sets to one lead.
The momentum was back with Nadal, who fought off two break points in the opening game of the fourth set and broke a tiring Djokovic with a heat-seeker of a forehand.
He backed it up for 3-0 and repeated it against a broken-spirited Djokovic for 5-1. Victory was Nadal's after three hours and 21 minutes when Djokovic buried a return in the net.
The triumph also meant that 34 of the last 35 Grand Slam finals have been won by the 'big four' of Nadal, Djokovic, Federer and Murray.