The victory puts Djokovic three Slam wins away from Nadal's 17 and six behind Federer's record 20.
An eight-time finalist in NY who had only previously lifted the trophy in 2011 and 2015, the Serbian was made to work hard on Sunday as Del Potro came from a break down in the second and third sets.
Amid increasing noise between points and serves, which prompted frequent interventions from chair umpire Alison Hughes, the previously assured Djokovic - who missed the tournament past year due to an elbow injury - appeared agitated.
Del Potro, 29, won the only Grand Slam title of his career by upsetting Federer in NY in 2009, but couldn't swing the upset Sunday.
"I guess he knew it was going to probably not be enough against some players, but he was happy enough playing this way, which I admire a lot".
Del Potro could take consolation, though, from the vast support he received. There was no reaction from Djokovic as he got the decisive break, no roar like the first two sets.
When he led 3-1 in the second, Djokovic appeared to be cruising to a 15th win in 19 attempts against del Potro.
Djokovic's most hard opponent this tournament has been the heat and humidity, so Sunday's cool and wet conditions, resulting in the roof being shut on Arthur Ashe Stadium, were perfectly to his liking.
Djokovic has not won as many majors as Federer, but 13 of his 14 Grand Slam titles have arrived after 2010, so he has benefitted from significantly larger winner's checks.
Djokovic had words of thanks for his family and coaching team for their help after he had an elbow operation last February.
After his latest performance, it's a safe bet Sampras is admiring Djokovic as well - along with many others.
Federer broke Sampras' record at Wimbledon in 2009, with Nadal also surpassing the American with victory at the 2017 French Open. And there could well be an encore as Djokovic had a momentary lapse in concentration while faced with the dual attack from the crowd and del Potro's groundstrokes.
While many hope del Potro gets that second major someday, including Djokovic - he is severely owed by the tennis gods - his foe was simply too good in the opening set.
This viral reaction was a response to the eighth game of the second set; a 20-minute, 22-point odyssey which became a microcosm of the match.
"I really wish him all the best".
Novak Djokovic and the WTA shared their opinions on what transpired between Serena Williams and chair umpire Carlos Ramos during Saturday's U.S. Open women's final.
The tournament in NY saw the big titles going to Naomi Osaka and Novak Djokovic, but it will be remembered for all manner of controversies and talking points.
"I want to keep making history, and make as much as possible", he explained.
"Difficult times, but you learn through adversity, " Djokovic said. "I'm glad I managed to do that".
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