However, Del Potro and his mighty forehand came to the party, striking back in spectacular fashion to level at 3-3, while the support for the giant Argentine appeared to rattle Djokovic's concentration levels.
His extended time away from the game may have denied the 29-year-old del Potro a chance to elbow his way in among the game's "Big Four" of Nadal, Federer, Djokovic, and Andy Murray.
A year after missing the 2017 US Open because of an injured right elbow that would require surgery, Djokovic showed that he is unquestionably back at his best and back at the top of tennis.
The crowd was roaring for sentimental favourite Del Potro - shut out of Grand Slam finals since his 2009 US Open triumph. "When they shout "Ole, ole, ole, ole", that's what I hear", he said of the raucous chants for Del Potro.
Playing on the same court where Pete Sampras claimed his 14th and final Grand Slam crown, Djokovic had endured more disappointment than joy on Arthur Ashe, mining just three titles from eight finals.
They are also atop another important ranking: most career Grand Slam titles by a man. Federer holds the record of 20, followed by Nadal with 17, and Djokovic, who equaled Pete Sampras at 14.
Naomi Osaka's family members and mentors expressed a flurry of emotions following her September 9 (Japan time) victory over Serena Williams in the U.S. Open tennis tournament final. Her mother Tamaki, meanwhile, shed tears with her daughter in the stands as they hugged each other following her victory, which gave her the honor of becoming the first Japanese to win a Grand Slam singles tennis title.
Serena Williams incident has umpires talking boycott
That sentiment has led to renewed talk among umpires of forming a union, an idea that has been around for years. The nascent boycott isn't aimed at Serena as much as it is at the Women's Tennis Association and U.S.
"We are proud to be close to these legends", Del Potro said.
The third and final set almost followed the same script, as Djokovic again broke del Potro to take a 3-1 lead only for the Argentinian to break back and level the set at 3-3.
Nadal stayed at No. 1 despite retiring from his semifinal last week, and Federer remained No. 2 after a fourth-round loss in NY.
Later, after winning a point, Djokovic put that finger to his ear, as if to say, "Who are you cheering for now?!" "I believe he'll be here again with the champion's trophy.
We reached the top after three hours", Djokovic recalled after landing the US Open title by beating Juan Martín del Potro on Sunday.
"I really felt for Serena".
In New York, while some of his fiercest rivals fell by the wayside over a bruising fortnight, Djokovic did not let the intense heat or any of his opponents push him off his path to a third title at Flushing Meadows.
With the Arthur Ashe Stadium roof closed as heavy rain swept NY, conditions were slow and sluggish.