6-3 victory over the 2009 victor under the roof at Arthur Ashe stadium - rain in NY meant cover was needed - gave the Serb a third crown at the US Open and 14th grand slam title overall.
The Serb now leads del Potro 15-4 in career meetings, and 5-0 in Grand Slam encounters.
The Serbian sixth seed is making his eighth U.S. Open final appearance, tying an professional era record, while Del Potro, seeded third, is playing in a Grand Slam final for just the second time.
Del Potro ultimately came up short in the men's final, despite a titanic effort, as the rejuvenated Djokovic produced a masterclass to claim his 14th grand slam title.
But the twist of the tale happened when leading 4-3, Djokovic broke Del Potro yet again to enforce a third break in the third set and set up the match on his serve.
But in that critical eight deuce game, the three break chances evaporated.
Del Potro - the third seed - had earlier lauded Djokovic, telling ESPN: "So happy to play in the final against this magnificent idol".
Djokovic is now level on 14 grand-slam titles with Pete Sampras and, in men's terms, behind only Rafael Nadal on 17 and Roger Federer's 20.
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For quite some time after that Djokovic looked towards Del Potro's singing friend with utmost anger, unable to get them out of his head and that showed on the court.
He said: "Pete Sampras is one of the biggest legends ever to play the game".
"I was crying until now", del Potro told reporters at the start of his news briefing.
Djokovic, who struggled with the NY humidity in the first two rounds, did not drop a set from the third round onwards. I will keep playing tennis for a few more years.
Ashleigh Barty and CoCo Vandeweghe have won the U.S. Open women's doubles final, beating Timea Babos and Kristina Mladenovic 3-6, 7-6, 7-6 at Arthur Ashe Stadium. Actually, today I am.
For world number three Del Potro, it was a heartbreaking experience coming in just his second Slam final, nine years after he was crowned US Open champion before a long battle with wrist injuries pushed him into depression and to the brink of retirement. "He has 14 (Grand Slams) already.
When they shout "Ole, ole, ole, ole", that's what I hear", he said of the raucous chants for Del Potro. "I was looking for winners with my forehand, backhand, but I couldn't make it, because Novak was there every time".
In all, the second set was a lengthy 95-minutes before ending for Djokovic in the tiebreaker, and saw both players leave the court for a change of clothes at its conclusion. "Now I have a feeling he's [catching] up with them", Vajda continued, slapping the back of his right hand on his left palm for emphasis. He finished with a flourish, taking the last three games.
The 2.4 overnight rating is up 32% from past year (1.9 for Sloane Stephens and Madison Keys of the U.S.) and 79% higher than 2016 (1.4 for Angelique Kerber vs. Karolina Pliskova).