Djokovic is trying for a third U.S. Open title and 14th major overall, which would tie Pete Sampras for third place on the career list.
Djokovic, 31, has earned five wins in 11 ATP Finals appearances with a record of 31-11, but missed last year's tournament due to an elbow injury.
With the Arthur Ashe Stadium roof closed as heavy rain swept NY, conditions were slow and sluggish.
Nadal hobbled out of a semi-final match against Del Potro after two sets.
Serbian tennis star Novak Djokovic defeated Juan Martin del Potro to clinch his third US Open title on Sunday. Cilic) in January, marking his 20th Grand Slam championship trophy, and the following month he captured the ABN AMRO World Tennis Tournament title in Rotterdam (d.
"I was playing nearly at the limit, all the time, looking for winners with my forehands, backhands, and I couldn't make it, " Del Potro said, "because Novak [was] there every time". "And so, so happy to be playing the final against this magnificent idol".
Juan Martín del Potro brought his own cheering section to the US Open, but in truth, the "gentle giant" from Argentina has the backing of the entire tennis world.
We started the tournament by asking the question as to whether the new wave of rising stars on the men's tour could finally start to make their mark on the Grand Slams.
"It is not easy to speak right now", Del Potro said on court.
That left Djokovic, who missed the U.S. Open previous year because of a right elbow injury, as the last man standing to defend the "Big Four's" title streak against a man who had broken it once before.
Osaka, who was up a set on Williams, saw the match descend into chaos midway through the second set when her opponent was warned for coaching, docked a point for smashing her racket then docked an entire game for calling Ramos a thief and a liar.
Even with Sunday's disappointing result, del Potro's performance in New York City was laudatory given what the Argentinian has gone through since his triumph at the US Open in 2009.
"I was close to (quitting) this sport because I couldn't find a way to fix my wrist problems", he said. Nadal is the first man to retire from a semifinal or final at the US Open since the professional era began in 1968.
Djokovic kept up the pressure with an early break in the second before Del Potro broke back to end the Serb's run of 23 consecutive holds.
"I just feel like, as Serena said in the closing ceremony, Osaka deserves to have her moment". But Novak deserved to take the trophy.
Newly-crowned US Open champion Novak Djokovic said he was inspired to take up tennis after watching Pete Sampras in action and that matching his Grand Slam record is a dream-come-true moment for him.
"I really felt for Serena".
[Saturday's] match showcased one of tennis's new stars as well as one of the greatest players of the game.