Yet Djokovic was ultimately too strong, his ability to counter his opponent's two biggest weapons - Del Potro's serve and forehand - proving key as he triumphed 6-3 7-6 (7-4) 6-3 in three hours and 16 minutes.
Djokovic particularly struggles in the hot and humid conditions that hit NY over much of the fortnight and looked out of sorts against Marton Fucsovics in the first round - splitting the first two sets, he trailed 4-2 in the third - Joao Sousa in the fourth and giant killer John Millman in the quarterfinals.
He is now set to rise to third in the ATP rankings behind Rafael Nadal and Roger Federer, the only two men to have claimed more slam titles, but can justifiably claim to be the best player in the world at present.
He missed last year´s tournament with an elbow injury which sent his career into a mini-crisis.
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South Africa's Lloyd Harris, who reached the main draw of Grand Slam for the first time at the US Open, moved up 14 spots to a career-high 131. "She's surpassed me to become a celebrity", he said.
Djokovic though fought off the noise and Del Potro's challenging tennis to eventually take the second in the tiebreak.
"What I said on the stage, you can lose or win a trophy, but the love from the crowd, it could be even bigger than the tournament", del Potro said.
He needed four sets to get past 41st-ranked Hungarian Marton Fucsovics in the first round and another to get past 61st-ranked American Tennys Sandgren in the second.
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Olivia Newton-John performs at Cobb Energy Centre on April 9, 2017, in Atlanta, Georgia. In 2013, a minor vehicle accident led to the discovery of a lump in her right shoulder.
Del Potro - the third seed - had earlier lauded Djokovic, telling ESPN: "So happy to play in the final against this magnificent idol".
Djokovic was better than del Potro on their many lengthy exchanges, using his trademark body-twisting, limb-splaying court coverage to get to almost every ball, sneakers squeaking around the blue court in Arthur Ashe Stadium, where the roof was closed because of rain. Tough thing for a chair umpire to deal with, as well. But Djokovic was in no mood to hang around, winning the last three games to clinch the crown. "Ole Ole Ole. Delpo, Delpo" reverberated around the stadium in support of Del Potro. Later, after winning a point, Djokovic put that finger to his ear, as if to say, "Who are you cheering for now?!" He made one last stand by breaking and holding for 3-all. But then came another gruelling rally which showed just how tough an athlete, how determined a competitor, and how devastating a returner Novak Djokovic is.
The win at Flushing Meadows enabled Djokovic to complete a Wimbledon-US Open double after lifting his fourth Wimbledon title earlier this year at the All England Club in London.
"I don't think it's (the right) time and place to get into other subjects", he said. Actually today I am.
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