It was Nadal's 13th Grand Slam singles title, moving him into third place all-time among men, just one shy of Pete Sampras's 14 and four behind Roger Federer's 17.
The contest was the 37th professional bout between the rivals -most for any head-to-head match-up in the Open Era, with Nadal entering the match holding a career win-loss advantage, 21-15.
Nadal is now behind Sampras and Federar in terms of singles Grand Slam titles
The Spaniard surged to an early lead, utilising aggressive shot-making to earn an early break. Spin and speed were factors that favoured the Spaniard, as he adjusted to the stadium winds and outslugged the Serb.
Nadal broke his opponent a second time to get to 5-2, the served out the set. In the first stanza, Nadal would commit just four unforced errors to Djokovic's 14.
After an hour of sluggish play, Djokovic awoke in the second set. While Nadal had been broken just once in 82 service games in his first six wins in the tournament, Djokovic broke the Spaniard twice in the second.
The Serb's shots started to find their range, and he started to hold his own in rallying with one of the best ground-strokers in the game.
What's more, his serve started to beome a more effective weapon. With more pop and renewed pep, Djokovic made it 5-3 with a forceful two-handed backhand at the net after Nadal tried to get too fine with a drop shot.
The top seed then held serve to even the match at a set apiece. The match turned in the third set. At 4-all, Djokovic was up triple break point at, but Nadal dug in and fought his way back to deuce, eventually saving three break points on his serve.
Djokovic got it to 30-0 on his serve in the next game, but Nadal stole the match's momentum with four straight points, the last coming with a down-the-line winner.
"It was disappointing that I dropped the third set, even though I felt like especially in first four, five games I was the one who was, you know, dictating the play," said Djokovic, who dropped to 1-4 in his career in the US Open men's final.
Nadal controlled the fourth and final set, breaking Djokovic twice to take the set 6-1, the dominating performance putting an exclamation point on his remarkable run to the title.
"Playing against Novak is a very special feeling a" probably nobody brings my game to that limit like Novak did, said Nadal, holding the trophy during his on-court victory address.A
Turning to his opponent, the victor said: "You are an amazing player, and you're having an amazing career. I'm sure that (you) will finish (your) career being one of the best in the history of tennis."
"He definitely deserved to win this match today and this trophy," said Djokovic of Nadal. "
Nadal collects $3.6 million in prize money for the win here, cashing in on the $1 million bonus afforded him for also winning this season's Emirates Airline US Open Series Bonus Challenge, matching the largest payout in US Open history.