The Spanish great used an impressive array of power moves and dazzling rallies to get past Djokovic 6-2, 3-6, 6-4, 6-1 in windy conditions at Arthur Ashe Stadium in New York.
The Serbian star, also seeking his second U.S. Open crown, fell in a 3-hour, 20-minute contest.
The match turned during the ninth game in the third set as Djokovic was leading 40-love but fell victim to a furious rally during which Nadal fought back to win the game and then went on to break the world No. 1 in the next game.
Nadal went on to breeze through the fourth set to take his second major of the season, improving to 22-0 on hard courts in 2013 and 60-3 overall -- all after missing seven months due to a knee injury.
"Playing against Novak is always a very special feeling," Nadal said after the match.
Nadal "deserved to win this match today and that trophy," Djokovic added.
Australian Open champion Djokovic fell to 6-6 all-time in Grand Slam finals, including a 1-4 mark at the U.S. Open.
Between them, the pair have won 12 of the last 15 major titles.