Rafael Nadal, 27, held on magnificently in the third set to go on and win a gripping contest 6-2 3-6 6-4 6-1 in three hours and 21 minutes.
One incredible 54-shot rally – the longest in the tournament by 20 shots – summed up a battle that thrilled the 23,000 spectators in Arthur Ashe Stadium.
Rafael Nadal has now won 13 Grand Slam singles titles and moves within one of Pete Sampras in the all-time list, with Roger Federer leading on 17.
And after missing last year’s US Open during a seven-month absence with a knee injury, Rafael Nadal is now set to regain the number one ranking.
“Having this success is amazing,” he said.
“I never expected it. That’s life and I’m lucky to have what I’m having.
“I really love the competition, I really love the sport. All my career I dreamed to be involved in matches like today. I enjoy every moment.
“These things are not forever. In a few years I won’t have this chance. I try my best, I have passion and that’s all I can do.”
Monday’s final was a predictably electrifying, punishing contest as Rafael Nadal and Novak Djokovic met for the 37th time – taking them past the rivalry of John McEnroe and Ivan Lendl to set a new record since the Open era began in 1968.
It was their sixth Grand Slam final and third at Flushing Meadows, after Rafael Nadal won in 2010 and Novak Djokovic took revenge in 2011.
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