The key was his success with a lung-busting 22-shot rally and he pocketed the set when the 29-year-old del Potro netted a forehand.
It's the 14 grand slam singles title for Djokovic, which draws him level with Pete Sampras on the all-time list, behind only Roger Federer and Rafael Nadal. Not against Djokovic, who always seemed to have all the answers.
It was a magnificent night of tennis from both players, where Djokovic's athleticism, court coverage and tennis brains came out triumphant against Del Potro's big serve and forehand.
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.
With the win on Sunday, Djokovic has extended his head-to-head record against Del Potro to 15-4 as the Argentine was unable to upstage the Serb.
Del Potro was looking at having to become the first man since Pancho Gonzales in 1949 to win the USA title from two sets down.
"I think most of all, the respect they had for other player, they never went over the line and that's something truly incredible tonight", Djokovic said at the presentation ceremony.
"I was playing nearly at my limit all the time, looking for winners with my forehands, backhands, and I couldn't make them because Novak was there every time", Del Potro said.
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When it ended, with Djokovic holding to 4-all, spectators began leaving their seats, perhaps thinking it was time for a changeover, even though it wasn't.
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. At one moment, he pressed his right index finger to his lips, as if to say, "Shhhhhhh!"
Djokovic went on to congratulate Del Potro for his achievements despite all the injury trouble and made a massively sporting gesture by saying he knew Del Potro will stand as champion at this podium one day. But that was that.
He had hit his peak, Vajda said, at "just at the right time".
His victory follows a Wimbledon title that announced his return to the game's top tier after a February surgery waylaid him for a few months.
Djokovic kept up the pressure with an early break in the second before Del Potro broke back to end the Serb's run of 23 consecutive holds.
Now he's backed that up at the U.S. Open, the fourth time in his career he won multiple majors in a season.
"Difficult times but you learn from adversity".
"I tried to take the best out of myself in those moments and get myself in this position".