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.
It was Djokovic's 15th win over the Argentine and fifth in five at the Slams.
A victory also means that 50 of the last 55 majors have been won 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.
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 was only the second set dropped by the Argentine at the tournament.
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.
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 tantalizing 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.
(This story has not been edited by Devdiscourse staff and is auto-generated from a syndicated feed.)