Djokovic, playing in his eighth final in New York and already the champion in 2011 and 2015, is now just three Slams behind Rafael Nadal and six back from the record 20 held by Roger Federer.
It will also see him rise to number three in the world behind Nadal and Federer -- the rankings again reflecting the 'Big Three' status they have shared for so long.
It was also the third time the 31-year-old Serb -- who missed last year's tournament with an elbow injury which sent his career into a mini-crisis -- completed the Wimbledon-US Open double.
For world number three Del Potro, it was a heartbreaking experience coming in just his second Slam final, nine years after he was crowned US Open champion.
It was Djokovic's 15th win over the Argentine and fifth in five at the Slams. Victory also means that 50 of the last 55 majors have been win by the 'Big Four' of Federer, Nadal, Djokovic and Andy Murray.
With the Arthur Ashe Stadium roof closed as heavy rain swept New York, conditions were slow and sluggish. After taking just two points off Del Potro's first three service games, Djokovic, in his eighth final in New York and 23rd at the majors, pounced to break for 5-3.
For Djokovic, it was an illustration of him growing into the championships as he took his run of consecutive sets won to 14, stretching back to the second round against Tennys Sandgren. 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.
He had three more chances in the eighth, all saved by Djokovic in a marathon 20-minute game which left even Hollywood superstar Meryl Streep clasping her head in astonishment.
The effort took its toll on a suddenly weary-looking Del Potro as a 95-minute set was claimed by Djokovic in the tiebreak.
Del Potro was looking at having to become the first man since Pancho Gonales in 1949 to win the US title from two sets down. Djokovic sprinted into a 3-1 lead in the third set before a battling Del Potro clung on, hitting back for 3-3.
But off the back of a 24-shot rally, Djokovic broke again for 5-3 and he was within tantalising touching distance of his 14th Grand Slam title, just three months after he had left Roland Garros in despair after a shattering quarter-final exit.
The crowd was roaring for sentimental favorite Del Potro -- shut out of Grand Slam finals since his 2009 US Open triumph. Djokovic said it was the kind of heavyweight clash he's learned to embrace. 'This might sound funny, but my nickname is Nole.
When they shout 'Ole, ole, ole, ole,' that's what I hear,' he said of the raucous chants for Del Potro. 'I thought it was electrifying in some stages of the match, especially in the second set when we went toe-to-toe. I had my corner, as well. When the roof is closed, trust me, it's very, very loud down there. It takes a lot of effort to actually stay poised in this moment. I'm glad I managed to do that.'
‘I OWE FEDERER, NADAL’
Novak Djokovic was thrilled to match Pete Sampras with a 14th Grand Slam title at the US Open on Sunday, but he said it's Roger Federer and Rafael Nadal who have made him the player he is.
“Pete Sampras is one of the biggest legends ever to play the game,” Djokovic said,”He was my childhood idol. He was someone I was looking up to. The first actual thing I saw related to tennis on the TV was his first or second Wimbledon championship. That inspired me to start playing tennis. There is a lot of significance of me being now shoulder to shoulder in terms of Grand Slam wins with him.”
Djokovic had tumbled down the rankings, slowed last year by an elbow injury and a loss of confidence that accompanied a 54-week title drought.
Since bursting out of the slump with an unexpected Wimbledon title he has gone from strength to strength, adding a long-awaited Cincinnati Masters title to his resume before adding the US Open title to those he won in 2011 and 2015.
Djokovic faced neither of his greatest rivals en route to the title in Flushing Meadows. Seeded to face Federer in the quarter-finals, he found himself instead across the net from John Millman after the unheralded Australian stunned the Swiss great.
Nadal hobbled out of a semi-final match against Del Potro after two sets. Djokovic would have relished taking on either -- or both, although he admits that early in his career that wasn't always the case.
“Maybe 10 years ago I would say I'm not so happy to be part of this era with Nadal and Federer,” he said.
“Today I really am. I feel like these guys, rivalries with these guys, matches with Federer and Nadal, have made me the player I am, have shaped me into the player I am today. I owe it to them.”