The Japanese world No. 21 was aiming to join countrywoman Naomi Osaka in the U.S Open finals, but lost to Djokovic in a straightforward match: 6-3, 6-4, 6-2.
Del Potro won the first semi-final earlier in the day after defending champion Rafa Nadal retired with a knee injury in the second set.
Djokovic, another player whose recent injury cost him time at the top of the tennis pyramid, won Wimbledon this year and is rounding into his elite form again.
Djokovic looked imperious from the outset as he dictated the running from the back of the court and remained in total control throughout.
Nishikori - the first Japanese man to reach a US Open semifinal in the Open era - was a finalist in NY in 2014.
Djokovic, who is 10 centimetres shorter, said del Potro can rise to the occasion of a big match and he is especially wary of his opponent's forehand and big serve.
However, one stat that doesn't bode well in Djokovic's favour is his record in NY when facing an opponent for the first time in the final.
Djokovic barely played in the second half of 2017 as his ailing body demanded a lengthy hiatus and the rejuvenated Serb now appears hungrier than ever, intent on making up for lost time by claiming a second Grand Slam title of the year. Then I think was little bit better.
Djokovic is bidding for his third title at Flushing Meadows and 14th Grand Slam trophy overall.
Tiger Woods ties course record with opening round 62 — BMW Championship
How fun was that? "I've hit hundreds of millions of putts with that thing". "I mean, Tony obviously is the guy right now". McIlroy had been a shot clear of Woods at nine-under par after 15 holes when Woods headed for the clubhouse.
Djokovic, who was forced to skip last year's tournament due to an elbow injury and returned to the tour this year after surgery, said he was thrilled to be back on the big stage.
"I think it was two-all in the first, 15-love, something like this in the first set, that I felt (something)", said Nadal.
Despite that record, Del Potro is under no illusions regarding the favourite for their tie.
"It means a lot to be back in the final", added Del Potro after his sixth win over Nadal, all on hard court. A big challenge, as well, because I've been fighting with many, many problems to get to this moment. I have tremendous respect for him as a person and a player.
Meanwhile, Del Potro reached his second Grand Slam final after waiting nine years after a wrist injury that threathened his carrer. "But I certainly felt the six months off gave me time to recharge my battery and think about how I want to continue playing the game of tennis". So Mike paired with Sock and they won Wimbledon in just their second event together.
Del Potro lost almost two years, undergoing three operations and fearing his career was finished. "That was the bad moment for me", said the 6-foot-6 (1.98-meter) Argentine with the 100 miles per hour (160 kph) forehand and 135 miles per hour (215 kph) serves.
Rafael NadalAfter seven years of struggles, Nadal is finally looking like a contender again at Wimbledon and is playing a lot like the man who reached his fifth final in 2011, except for this flat-faced fall.