The 31-year-old beat Argentinian world number three Del Potro with a 6-3, 7-6 (7/4), 6-3 taking him level with Pete Sampras´s mark of 14 Grand Slams.
It was Djokovic´s 15th win over the Argentine and his fifth in five at the Slams.
The Serbian tennis star, the champion in 2011 and 2015, was playing his eighth final.
Djokovic is now just three Slams behind Rafael Nadal and six back from the record 20 held by Roger Federer.
????????????@djokernole defeats Del Potro 6-3, 7-6, 6-3 to win his 3rd title in Flushing Meadows!September 9, 2018
He now ties Pete Sampras for third place all-time on the Grand Slam singles titles list with 14.#USOpen pic.twitter.com/xwzzmr22E0
He missed last year´s tournament with an elbow injury which sent his career into a mini-crisis.