His returns and defense-to-offense skills as impeccable as ever, Djokovic collected his 14th Grand Slam title and second in a row by getting through every crucial moment for a 6-3, 7-6 (4), 6-3 victory over 2009 champion del Potro at Flushing Meadows.
Djokovic has picked up a further 12 majors - a win tonight would take him joint-third in the all-time list with 14 - while Del Potro's career has been decimated by injury, making this his first slam final since that win in 2009.
Yet Djokovic was ultimately too strong, his ability to counter his opponent's two biggest weapons - Del Potro's serve and forehand - proving key as he triumphed 6-3 7-6 (7-4) 6-3 in three hours and 16 minutes.
Both men had one grand-slam title to their name, but for some Del Potro looked the safer bet.
Just like last night's women's singles final, the match was played under closed roof with rain in NY.
Things looked ominous for Del Potro as Djokovic seized control early on, moving magnificently and constructing a number of superb points with precision striking.
No controversy here: Novak Djokovic is the U.S. Open men's singles champion. The game lasted so long that fans left their seats when it finished, assuming two games had been played in that amount of time and that it was a changeover.
The Argentine put his admiration aside Sunday and made it hard for Djokovic to gain an edge, despite the score of the first set.
The Serb appeared to be on course for an easy victory when he went up a break in the second set to go up 6-3, 3-1.
Head-to-head, Djokovic leads Del Potro 14-4, but the Argentinian is a powerhouse.
"I was playing nearly at my limit all the time, looking for winners with my forehands, backhands, and I couldn't make them because Novak was there every time", Del Potro said. In the years between toppling Roger Federer in the 2009 final and Sunday's match, del Potro almost quit tennis after undergoing four wrist surgeries, three of them on his left wrist, that left him in a deep depression and had him seriously weighing retirement.
The third set followed the pattern of the second, where Djokovic took an early break to go 3-1 up in the set.
The noise levels inside the Arthur Ashe Stadium was deafening as Djokovic and Del Potro got the crowd roaring with their display on-court.
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.