Djokovic beat Del Potro, who has had his own injury issues, 6-3 7-6 (7-4) 6-3, and in turn goes level with his hero Pete Sampras or winning 14 career Slam titles.
Wimbledon champion Djokovic, playing in his 11th US Open semi-final, claimed a 15th win in 17 clashes against Nishikori.
The powerful player couldn't hit the ball hard enough with his backhand to threaten top players, let alone the rulers of the sport like Federer, Djokovic and Rafael Nadal.
Del Potro, the 29-year-old Argentinian who won the 2009 Open, is back at his best after a series of wrist surgeries, ranked a career high No. 3.
The second set immediately saw the Argentine under pressure on his serve, and though he managed to fend off Djokovic in game one, the relentless pressure told in game three as Del Potro sprayed two forehand errors to lose serve again.
"I think it's time to take a break, to see how my body feels for the future, and then be ready for the next one".
After both players exchanged earlier service breaks in the second set, it became key that Djokovic held onto his serve in the eighth game, staving off three break points in the 22-point game that lasted 20 minutes, 32 seconds.
Del Potro - the third seed - had earlier lauded Djokovic, telling ESPN: "So happy to play in the final against this magnificent idol".
Something in the Alpine air clearly agreed with him, though, and he went on to triumph at Wimbledon, the U.S. Open tune-up in Cincinnati and then in NY to grab his 14th career Grand Slam title, putting him third on the all-time list.
Djokovic's year got off to a less-than-ideal start, the Serbian set off on a five-day hike in the French Alps that proved transformative.
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Djokovic has only ever lost one match from more than 200 when he has led by two sets - to Austria's Jurgen Melzer at the 2010 French Open - but there was no sign of that happening again. "I am just one of the guys that have lucky to be in the same era as them, and it's great", he further added.
Del Potro was looking at having to become the first man since Pancho Gonales in 1949 to win the USA title from two sets down. I thought of tennis, thought of the emotion that tennis provokes in me.
The first violation given to Williams was for coaching, which isn't allowed during any men's matches but is permitted on the women's tour except in grand slam tournaments. Actually, today I am.
Del Potro said he felt many of his shots would have been winners against players other than Djokovic.
'I have utmost respect for what they have achieved on the court, but also the champions, role models they are off the court. I had my opportunities during second and third set.
"I didn't expect to get to another Grand Slam final in my favourite tournament".
But he had a 4-14 losing record against Djokovic, including four at the Slams - two of them at the US Open in 2007 and 2012.
The duo saved three championship points in the deciding set in a match that took more than 2½ hours to complete.