Crowd-favourite Del Potro impressively dismissed the challenge of Borna Coric in the fourth round and the Argentine has yet to drop a set in this year's championship.
The 2009 champion has been one of the most consistent players in the tournament so far and he knows that if he plays his best game here, it should be enough to beat Isner having won seven of their previous 11 encounters.
Del Potro defeated Isner without dropping a set in their most recent meeting at the French Open earlier this year, and although that was on a different surface, that victory will be fresh in his mind as he aims to reach the semi-finals in Flushing Meadows for the second year running.
Isner's route to the quarter-final has not been quite so straightforward having been taken to five sets twice and four sets once, with his most recent match being a nip-and-tuck battle with Milos Raonic which the American took in a decider.
The home-favourite's biggest weapon is undoubtedly his serve and that has been as prolific as ever so far. 112 aces have come from the Isner racket and he comfortably leads this statistic for the tournament.
Despite his recent loss to Del Potro in Paris, Isner has been the victor in their last two meetings on hard courts, including in Miami earlier this year where the American went on to claim the Masters title.
Two of the most powerful players on tour meet in the quarter-finals and history tells us this is likely to be an incredibly tight match with one or two tie-breaks to be expected. Isner's serve will be key to his chances as he will look for free points as often as possible due to Del Potro's edge when it comes to baseline rallies. The Argentine will target Isner's backhand and look to set up winners for his potent forehand which, more often than not, hits its target.
Isner has clocked significantly more time on court so far and that just swings this contest in favour of the fresher Del Potro, who looks in good enough form to reach his second consecutive semi-final in New York via a four or five-set win.