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.
While Djokovic laid on the ground in ecstasy Sunday, del Potro sat in his chair and cried. He was, in short, out of sorts.
Del Potro is forced into an error on the next point, but he digs out a drop shot on the next point and Djokovic puts a backhand volley wide of the mark.
Del Potro's movement went from nimble to clunky after that.
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.
Tetsuo Osaka said he saw his granddaughter's match on television as the crowd cheered for the former World No. 1 player Williams, and booed when Osaka won.
"Life showed me that it takes time for good things, it takes time to really build them, for things to fall into place".
"He's my idol. Pete, I love you, " Djokovic said.
But del Potro not only stuck with it, he surged up to a career-high No. 3 in the rankings last month on the strength of a semifinal run at the French Open and a victory over Federer to win Indian Wells. With his wrist injuries, coming back, still having belief and faith in himself that one day he will be a top player and fighting for grand slams. "I'm glad I managed to do that", Djokovic added.
However, Del Potro and his mighty forehand came to the party, striking back in spectacular fashion to level at 3-3, while the support for the giant Argentine appeared to rattle Djokovic's concentration levels.
Things looked ominous for Del Potro as Djokovic seized control early on, moving magnificently and constructing a number of superb points with precision striking.
"This might sound amusing, but my nickname is Nole".
Deuce and the second straight Djokovic service game where he's been pushed. That prompted to chair umpire Alison Hughes to chastise them. Not against Djokovic, who always seemed to have all the answers. At one moment, he pressed his right index finger to his lips, as if to say, "Shhhhhhh!"
The tiebreaker was resolved thanks to more del Potro miscues on his forehand side, as he looked more and more tired. But that was that.
Quite a few had written off Djokovic when the Serb was sidelined due to elbow issues in 2017. He tried to return at the start of this season but couldn't and opted for surgery. He knows he is one of my friends on Tour and knows he is one player I want to see win titles. "In terms of results, I played finals of Queen's, won Wimbledon, won Cincinnati, and won US Open".
Djokovic said it was the kind of heavyweight clash he's learned to embrace.