Del Potro was unable to stop the rejuvenated Djokovic, but there was plenty of love in the air afterwards at Flushing Meadows - where both players praised each other.
The 31-year-old Serb won 6-3 7-6 (7-4) 6-3 to earn his third triumph in NY and equal American great Pete Sampras' haul of major trophies.
Djokovic has now entered the top three of the list of most Grand Slam titles in men's singles tennis history, tied at the third sport with Pete Sampras.
He missed last year´s tournament with an elbow injury which sent his career into a mini-crisis. Most predicted the Spaniard as the one most capable of surviving intensely hot, humid conditions as well as night matches that stretch into the early-morning hours at the year's final Grand Slam.
"When the roof is closed, trust me, it's very, very loud down there".
Djokovic sprinted into a 3-1 lead in the third set before a battling Del Potro clung on, hitting back for 3-3.
Equalling Sampras was particularly special for Djokovic, who said: "Pete Sampras is one of the biggest legends ever to play the game". Del port has backed Djokovic to surpass Federer's mark of 20 Grand Slams.
With all the singing and noise levels inside the stadium, it felt to Djokovic like he was at a football match but he thanked the fans of both sides for creating such an wonderful atmosphere.
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There may have been no game more important to Djokovic's win or simply entertaining than the eighth game of the second set. "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". That prompted to chair umpire Alison Hughes to chastise them.
But seemingly temporarily distracted by del Potro's supporters getting louder, not to mention the world No. 3's better play, he was broken back for 3-3. At one moment, he pressed his right index finger to his lips, as if to say, "Shhhhhhh!"
When it ended, thanks to a three-game closing run by Djokovic, he flung his racket away and landed on his back, arms and legs spread wide.
Djokovic had words of thanks for his family and coaching team for their help after he had an elbow operation last February.
The Argentine put his admiration aside Sunday and made it hard for Djokovic to gain an edge, despite the score of the first set.
'Cecchinato has made me realize, a lot of things after that loss to him in Roland Garros', Djokovic admitted. 'I was very, very disappointed with my performance that day.
"Difficult times but you learn from adversity".
The two players had battled on the court 18 times before Sunday's final at the U.S. Open, with Djokovic earning 14 victories against the 29-year-old and winning six of the last seven.