The Argentinian with the big forehand and even bigger heart defied fatigue and illness to defeat Federer 7-5 3-6 7-6 (10/8) 6-4 in a dramatic quarter-final.
Eight years ago, Del Potro won his only grand slam title in New York by beating Nadal in the semi-finals and Federer in the final.
Given the circumstances and all the injury problems he has gone through in the intervening years, it would be a significantly more remarkable achievement if he could repeat the feat.
Not least because on Monday he almost retired down two sets to love to Dominic Thiem and struggling with a heavy cold.
The effort of his epic comeback, inspired by his legion of fans, as well as the victory over Federer, will undoubtedly have taken its toll.
Del Potro said: "I think I am recovering well. I did what the doctor says, all the treatments, and I played just free. I didn't have anything to lose against Federer, so I did my best match of the tournament.
"I played a very smart game during the whole match. It's so important to me to beat him another time in this amazing tournament.
"Now is still a harder match. Physically I'm not in the perfect conditions, but when you play semi-finals of the grand slam, everything can happen.
"So you must be ready for the chance and playing against Rafa in my favourite tournament, I will try to enjoy the atmosphere, the game, and I know if I play my best tennis, I could be a danger for him.
"I like to play against him when I'm in good conditions. But it's not the case at this moment. Fo r sure I will try to make winners with my forehands and don't run too much, because my legs are tired."
The focus of Nadal's press conference, which took place before the second semi-final, was so much on a potential clash with Federer that, asked what he most admired about the Swiss, his great rival blurted out: "I don't want to look like I'm going to be his boyfriend."
There is not as much history between Nadal and Del Potro, although they have met 13 times, with Nadal winning eight but Del Potro coming out on top of their only recent clash in the semi-finals of the Olympics last year.
Nadal has found his form as the tournament has gone on and crushed Andrey Rublev in the quarter-finals for the loss of only five games.
He said of Del Potro: " I need to be very focused with my serve and play aggressive, because if you let him play from good positions with his forehand, you are dead."
Amid all the focus on Nadal, Federer and now Del Potro, the first semi-final between Pablo Carreno Busta and Kevin Anderson has understandably been overshadowed, but it is the chance of a lifetime for both men.
Neither has ever made the last four of a slam before, and whoever wins will be one of the most unlikely finalists for many years.
Anderson ended the hopes of American Sam Querrey in the quarter-finals and is the first South African player to make the last four at a grand slam since Wayne Ferreira 14 years ago.
Although he has lived in the United States for a long time, there has been a lot of excitement back home, with Anderson receiving messages from Ferreira and golfers Ernie Els and Louis Oosthuizen.
He said: " My biggest hope is that I'm able to inspire kids to play the sport. It's very tough coming from South Africa, far from the scene. It makes me feel good that I can hopefully fly a flag and show kids especially that if you work hard you can get there."
Anderson won both his previous meetings against Carreno Busta, including in Montreal last month.
The 12th seed said: "Maybe it will be difficult to play against him again, but I think I am playing with more confidence. I am playing better."