Nadal, bidding for a fourth title in NY and 18th major, had spent the best part of 16 hours getting to the semi-finals.
As his opponent limped increasingly heavily between points, Del Potro ruthlessly fired in winners, his backhand proving nearly as potent as his famously magnificent forehand.
The Serb became just the third man in the Open Era to reach eight finals in NY on Friday with another straight sets win over Kei Nishikori, matching Pete Sampras and Ivan Lendl.
Loss of motivation after winning all there was to win, personal problems away from the court and an elbow injury that required surgery were all partly to blame for the decline of the then world No 1, who lost the spot to Andy Murray in November 2016 and has not had it back since.
Rafael Nadal was forced to retire after the second set.
Novak Djokovic hailed Juan Martin del Potro as a "gentle giant" but he'll have no hesitation in attempting to cut his close friend down to size in Sunday's US Open final.
Finally, after dropping the second he removed his headband, put his racquet in his bag and went to shake del Potro's hand. I think I've played more than 10 semifinals here. "But it definitely makes me realize that, OK, I can definitely do my best if he can, too".
In his lengthy efforts to fully recover from his wrist injuries, del Potro almost gave up tennis in 2015. That shows the quality that he has, especially in the big matches.
He added: "I mean, he's a gentle giant". "But I think that is completely in the past, and now I'm having a good present, looking forward for the future". I said too my box immediately that I felt something on the knee. He is 14-2 against Nishikori, including a victory in the quarter-finals at Wimbledon. Nadal bested the Argentine in their meeting past year.
He has slowly made his way back in 2018, gradually gaining confidence with a quarter-final run at Wimbledon and his last-four appearance here. "Just one player playing, the other staying on one side of the court", Nadal said.
"One of the keys of the match will be [my] return, how well I can return, how many returns I can get back in play, but also try to have some depth in that return, and how accurately I can serve myself". His knee was also taped in the first set. "I was a kid then and now I'm much older". "Even when he dropped his ranking and started to, you know, work his way up, but we all knew that he has a capacity and a quality to get to the point where he is at the moment". It was so hard to keep playing that way. "Serve, return, groundstrokes - he was playing aggressive and I didn't have much energy to stay with him".
Nadal already had the admiration of tennis fans for his relentless approach and unyielding competitive spirit. He and Nadal have developed a respect for each other.
"He's a gentle giant", the 31-year-old Serb said of the 6ft 6in (1.98m) Del Potro affectionately dubbed the "Tower of Tandil" after his home town.