With conditions much cooler than they have been for most of the tournament, Djokovic finally looked comfortable on Arthur Ashe Stadium and responded with his best performance to defeat Nishikori 6-3 6-4 6-2.
The triumph for the sixth seed saw him complete the Wimbledon-US Open double for a third time and he remains only the eighth player to have achieved the feat in a calendar year.
On the day of the final, Djokovic just showed why he was the holder of 13 Grand Slam titles.
The victory will also see Djokovic rise to No.3 in the world behind Nadal and Federer - the rankings again reflecting the "Big Three" status they have shared for so long.
After taking just two points off Del Potro's first three service games, Djokovic, in his 23rd final at the majors, pounced to break for 5-3. While Djokovic, who defeated Juan Martin del Potro to win the men's title, rose to 3rd in the ATP rankings, Osaka made a jump of 12 places to acquire the seventh spot in WTA rankings.
Del Potro - the third seed - had earlier lauded Djokovic, telling ESPN: "So happy to play in the final against this magnificent idol".
This is Djokovic's second straight Grand Slam singles title this season following Wimbledon 2018 and a 14th overall to tie American Pete Sampras for third all-time.
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Early in the tournament the extreme heat and humid conditions in NY were clearly troubling Djokovic. However, unlike Saturday night, this match remained all about tennis and the brute quality that the two players put on the court.
"I guess we'll be hiking some more very soon", he added with a smile. And now she's the first player from Japan to win one.
The 16-year age gap between Williams and Osaka was the second biggest in the Open Era for a women's final, next only to Monica Seles (17) vs. Martina Navratilova (34) at the 1991 U.S. Open. I thought I came in today from the first point with a great intensity, great focus. "I really do", said Djokovic, who gave his pal a hug at the net, and then went over to console del Potro as he wiped away tears at his sideline seat.
"To be honest, I was crying till now", Del Potro said at a news conference.
"He has 14 already. I was looking for winners with my forehand, backhand, but I couldn't make it, because Novak was there every time".
Victories that finished after 2 a.m. for 2014 champ Marin Cilic (against 19-year-old Alex de Minaur) and Nadal (against Dominic Thiem.) Nadal's retirement from his semifinal against del Potro because of an injured right knee.
Now he is back up to three and within striking distance of Nadal in the race to finish the season ranked world number one. I agree that the girls have to be treated the same as the men, win the same money.
Four easy holds later and it was onto a tiebreaker that decided the second set, and ultimately the course of the match as Djokovic capitalised on several bad errors from his opponent to win it 7-4.