Nishikori was taken to five sets by Marin Cilic - the man who beat him in the 2014 final - in Wednesday's quarter-final but he came through to reach the third Grand Slam semi-final of his career.
His previous two have also come at the US Open, and on one of those occasions (2014) he defeated Djokovic in four sets so he will be aiming for a repeat of that performance.
Unfortunately for Nishikori, Djokovic has been the victor in all 13 meetings since that match and has generally dominated this rivalry, so the Japanese player knows he is up against it here.
Despite again appearing to struggle with the humid conditions, Djokovic battled past Roger Federer's conqueror John Millman in straight sets on Wednesday to continue his bid for a third US Open title.
The Serb's favourable record against Nishikori will give him great belief that he can make it through to an eighth final at Flushing Meadows and with the temperatures set to cool down in New York, that will only help his cause.
A key factor behind his dominance in this rivalry is that his strength targets his opponent's weakness. Djokovic is the greatest returner in the history of the game, and he uses that to great effect against Nishikori who doesn't possess a serve that can really hurt the Serb.
Nishikori and Djokovic possess very similar games in that they are both great defenders from the back of the court, they move incredibly well and they like to dictate from the baseline, but the fact of the matter is that Djokovic is superior in all those departments and has a few extra weapons in his arsenal that Nishikori doesn't possess.
Nishikori has enough about him to make this a competitive affair and we should see plenty of long rallies, but if Djokovic plays to his best then there will only be one winner. A straight-sets win is not out of the question for the two-time champion, whose incredible consistency at the US Open is set to continue.
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