Djokovic also was the champion in NY in 2011 and 2015.
Djokovic was soon 3-1 up in the second set before Del Potro carved out his first break point of the match to level at 3-3. That Williams lost a point, then a game, and was fined $17,000 are what will be remembered about that final.
The tension lifted in a marathon eighth game that took 20 minutes to decide, Djokovic finally holding to keep the set on serve at 4-4.
Argentine third seed Del Potro, 29, was playing his first Grand Slam final since winning the 2009 US Open, having nearly quit the game in 2015 because of multiple wrist injures. But Djokovic was in no mood to hang around, winning the last three games to clinch the crown.
Djokovic pulled into a tie with American Pete Sampras on the all-time men's leaderboard in majors and now only trails his two contemporaries and greatest rivals, Roger Federer and Rafael Nadal. It was also just the latest Slam for the "Big 3" of men's tennis - Djokovic, Rafael Nadal, and Roger Federer.
Djokovic, who was seeded sixth, is one of only eight men to win the Wimbledon-US Open double and has now accomplished that feat for a third time.
"If you told me in February this year when I got the surgery that I'll win Wimbledon, US Open, and Cincinnati, it would be hard to believe", said Djokovic, referring to August's Cincinnati Masters that completed his Masters collection. "I don't know when will be my last tournament in this career, but I'm excited to keep surprising myself doing things like this".
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He called on the governor of Puerto Rico Ricardo Rossello to launch an official independent investigation into the incident. The historical relationship between Puerto Rico and Washington is unfair and unAmerican. "We're ready.
After a rough start to his season, Djokovic will go into the 2019 Australian Open in January looking to win his third straight major.
"Today I really am".
Djokovic, the No. 6 seed, missed this tournament a year ago as he struggled with an elbow injury that ultimately required surgery. Not against Djokovic, who always seemed to have all the answers - and who said he convinced himself that all of those "Oles" were actually people calling out his own nickname, "Nole".
In one charge at the net, Djokovic picked a del Potro volley off his toes and sent back a victor.
Statistically, the men's final was relatively even.
It was a brief request, though, unlike her many other pleas for quiet, mainly as fans were shouting and chanting and clapping in support of del Potro. But then he was broken in his next game.
While Streep was beside herself, Jerry Seinfeld had more of a skeptical look. For Djokovic, too. "You learn when you're down and things are not working out as you want them to", he said.
Leading 4-3, Djokovic caught Del Potro off guard with his exceptional patience and strong strokes to break Del Potro's serve. Of course I'm sad to lose but I'm happy for Novak as well.