Novak Djokovic kept getting the ball back, so del Potro would take a bigger whack, trying to find some spot in the corner of the court that would be uncovered.
A focused Djokovic continued to apply pressure in the third set until Del Potro finally cracked on serve to fall behind 5-3, with the Serb closing out the match with a ferocious overhead victor.
He missed last year´s tournament with an elbow injury which sent his career into a mini-crisis.
"There is a lot of significance of me being now shoulder to shoulder in terms of Grand Slam wins with him. I really am", he said.
Djokovic's coach, Marian Vajda, called that moment the match's "turning point, obviously".
"When I had the surgery on my elbow I could truly understand what Juan Martin was going through", Djokovic said.
Del Potro backed Djokovic to surpass Federer's mark of 20 Slams.
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At the same time , I can't say whether we would have done it or not, so I don't want to sound churlish. He criticized the media for what he said were its efforts to "undermine this administration".
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Djokovic has only ever lost one match from more than 200 when he has led by two sets - to Austria's Jurgen Melzer at the 2010 French Open - but there was no sign of that happening again.
Federer lost in the fourth round in NY, while Nadal retired from his semifinal against del Potro because of a bad right knee. He finished with a flourish, taking the last three games. Tough thing for a chair umpire to deal with, as well.
But seemingly temporarily distracted by del Potro's supporters getting louder, not to mention the world No. 3's better play, he was broken back for 3-3. It all bothered Djokovic, who started yelling and gesturing toward the seats.
While Johanna Konta and Kyle Edmund have both excelled in their own right, neither made it past the first round here, and no British singles player has made it into the second week at four of the last five slams.
"I was very, very disappointed with my performance that day", Djokovic recalled Sunday, explaining that he went hiking in the mountains in France to clear his head after that setback.
"Difficult times but you learn from adversity".
"The worst part to me is the chances that I couldn't make but then when you see a friend holding the trophy, it's good, too".
The runner-up, Serena Williams, is back in the top 20 at No. 16, after being No. 26 before the U.S. Open - and outside the top 400 as recently as May, following the former No. 1's time away because she had a baby.