The 31-year-old Serb won 6-3 7-6 (7-4) 6-3 to earn his third triumph in New York and equal American great Pete Sampras’ haul of major trophies.
Djokovic, who won Wimbledon in July, will climb to fourth in the world after back-to-back Grand Slam victories.
Only great rivals Roger Federer (20) and Rafael Nadal (17) have won more.
Argentine third seed Del Potro, 29, was playing his first Grand Slam final since winning the 2009 US Open, having almost quit the game in 2015 because of multiple wrist injures.
A fairytale finish at Flushing Meadows was not to be, however, as former world number one Djokovic’s quality shone through.
Djokovic, who was seeded sixth, is one of only eight men to win the Wimbledon-US Open double and has now accomplished that feat for a third time.
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