A series of missed forehands by del Potro in the tiebreaker put Djokovic back on course and he finished with a flourish, taking the last three games - sealing the title on his first match point.
Djokovic had lost five previous finals at Flushing Meadows, but he was determined to make amends for his lack of trophies in NY as his defensive ability combined with his ruthless prowess saw him break in the fourth game, although Del Potro was not in the mood to give up so easily as he hit straight back.
When another forehand error cost Del Potro his serve early in the second, all the momentum was with Djokovic.
The key was his success with a lung-busting 22-shot rally and he pocketed the set when the 29-year-old del Potro netted a forehand.
"We are proud to be close to these legends", Del Potro said. "But I love you too, guys", he told the crowd.
Djokovic and Del Potro walked on Arthur Ashe Stadium court with the Billie Jean King National Tennis Center still buzzing over the controversial women's final on Saturday, won by Japan's Naomi Osaka after Serena Williams incurred three code violations.
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.
The tiebreaker was resolved thanks to more del Potro miscues on his forehand side, as he looked more and more tired.
With the quality of tennis only on the rise, the noise level inside the Arthur Ashe Stadium was deafening.
Djokovic collects $3.8 million and his third U.S. Open championship. He depended on his hometown friends, a group of whom have been in NY throughout the fortnight to lead cheers in Arthur Ashe Stadium, and worked his way back to the final at his favorite ATP Tour event. "But I'm happy for Novak and his team".
"When I had my surgery I could truly understand what Juan Martin was going through when he had surgeries that kept him away from the tour for two or three years", added Djokovic.
"Difficult times, but you learn through adversity", Djokovic said.
"I want to say Pete, I love you, you're my idol", said Djokovic of Sampras. He made one last stand by breaking and holding for 3-all.
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.
"I believe he'll be here again with the champion's trophy".