The 31-year-old Serb won 6-3 7-6 (7-4) 6-3 to earn his third triumph in NY and equal American great Pete Sampras' haul of major trophies.
There was a time when Pete Sampras's tally of 14 Grand Slam singles titles - the last of which came at the U.S. Open in 2002 - seemed like the acme of sporting achievement in men's tennis.
When Djokovic won his 13th Grand Slam at Wimbledon in July it was particularly pleasing as it was his first success at a major since he finally picked up the missing French Open trophy he so relished in 2016. Roger Federer has 20 titles and Rafael Nadal 17.
Argentine third seed Del Potro had been seeking first Grand Slam title since 2009.
Del Potro had a 3-1 lead in the tiebreaker before Djokovic recovered to take it.
The two reached deuce eight different times, with Djokovic saving three break points.
He needed his right knee strapped after the seventh game before gallantly fighting off two set points in the 10th game, breaking Del Potro who was serving for the set.
Del Potro - the third seed - had earlier lauded Djokovic, telling ESPN: "So happy to play in the final against this magnificent idol".
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. I feel like these guys, rivalries with them, matches with Federer and Nadal, have made me the player I am, have shaped me into the player I am today. "To be honest, I was crying till now", Del Potro said as he began his post-match press conference.
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Djokovic, who struggled with the NY humidity in the first two rounds, did not drop a set from the third round onwards.
"I took the risks with my forehand because it was the only way to beat this kind of player". I agree that the girls have to be treated the same as the men, win the same money. "He's playing tennis of his life, without a doubt, in the last 15 months", Djokovic said on Friday of his "dear friend" Del Potro.
"When I had my surgery I could truly understand what Juan Martin was going through", Djokovic said after the win.
After she was given a code violation for coaching in the second game of the second set by Ramos, a fuming Williams told the umpire that she "never cheated" and "would rather lose" than do that. I think we have pushed each other to the limit every time we get to play each other.
He was also taking longer and longer to serve, but dug deep to hold for 4-4 in a hugely dramatic game lasting just over 20 minutes. That victory established a career Grand Slam for the Serb, completing his collection of winning at least once at each of the four Slams.
It was the ninth consecutive slam semi-final that the 31-year-old has won and sends him through to a 23rd final.
But he had a 4-14 losing record against Djokovic, including four at the Slams - two of them at the US Open in 2007 and 2012.