A 61-minute set ended six points later after a Nadal forehand made Djokovic lunge and nearly do the splits and his reply went long.
Nadal bent down and pumped his fist four times. Djokovic glanced over to his players' box and walked, head down, to the sideline.
The fourth set was academic after Nadal broke Djokovic in the second game.
"It's obvious that in the important moments, he played better tennis, and that's why he deserved to win," Djokovic said.
Djokovic will still leave New York ranked first — a hollow consolation that won't last that long if Nadal keeps up his dominance on hard courts. He improved to 22-0 on the season, while Djokovic has more wins (31) but picked up his fifth and most painful loss on the surface in front of 23,000 in Arthur Ashe Stadium.
"I wish I'd won at least one title more, considering the fact I played two finals," Djokovic said, mentioning the two losses.
He opened the Grand Slam season with the title in Australia, while Nadal was still on the sideline with a stomach virus and also nursing his injured left knee back to 100 percent.
Djokovic lost a 9-7 fifth set to Nadal in the French Open semifinal, then fell in three sets to Andy Murray at Wimbledon.
The four-set loss to Nadal was reminiscent of the first time they met in the U.S. Open final, back in 2010, when it was also Nadal in four. It sparked Djokovic on to one of the best seasons ever. He went 70-6 in 2011 and won three of the four Grand Slams, capping it with a victory over Nadal at Flushing Meadows.
Could this latest loss produce a repeat?
"I have to," Djokovic said. "It's part of my life."
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