Djokovic then won the tie-break from 1-3 down to clinch a 95-minute set and, although Del Potro also threatened a comeback in the third, there was no doubt who was the stronger player.
Djokovic faced similar questions about whether he'd ever get back to another major final with his elbow woes, but after his triumph at Wimbledon in July, and with the more heralded - and older - Rafael Nadal and Roger Federer showing signs of slowing down, another reign of the Djoker looks very real in men's tennis.
That left Djokovic, who missed the U.S. Open a year ago because of a right elbow injury, as the last man standing to defend the "Big Four's" title streak against a man who had broken it once before.
Britain's Alison Hughes, the second woman to umpire a U.S. Open men's singles final, kept a low profile as the two former champions went to work. It's unbelievable. I don't feel sad that I couldn't win Grand Slams because of them.
Novak Djokovic overcame Juan Martin del Potro 6-3 7-6 (7-4) 6-3 in Sunday's final to secure his 14th Grand Slam title.
Djokovic was soon 3-1 up in the second set before Del Potro carved out his first break point of the match to level at 3-3.
Federer's haul of 20 Grand Slam titles is more than any other man in history - six more than Djokovic, who only also trails Rafael Nadal and Pete Sampras in terms of major wins.
Juan Martín del Potro brought his own cheering section to the US Open, but in truth, the "gentle giant" from Argentina has the backing of the entire tennis world.
"If you told me in February this year when I got the surgery that I'll win Wimbledon, US Open, and Cincinnati, it would be hard to believe", he said. With his wrist injuries, coming back, still having belief and faith in himself that one day he will be a top player and fighting for grand slams.
But del Potro not only stuck with it, he surged up to a career-high No. 3 in the rankings last month on the strength of a semifinal run at the French Open and a victory over Federer to win Indian Wells.
Since playing on the grass at Queen's Club in June, Djokovic has only lost two matches, while he extended his imposing winning record over Del Potro to 15-4.
"Reaching finals, winning titles, having my highest ranking ever in this moment, everything is nearly ideal", Del Potro said. "I think that's why people love him". "I know that he will be here again with the champions trophy". "I just want to create from this moment onwards the most I can create for myself, to get the best out of myself in every possible moment".
It is Djokovic's thid U.S. Open title and first since 2015.
Amidst the searing heat and disturbing humidity of NY for the past two weeks, Djokovic battled through and rose above it all to shine under the Arthur Ashe Stadium lights for the third time.