The 31-year-old Spaniard, the 2010 and 2013 champion in New York, will be playing in his 23rd Slam final and third this year, looking to add the US title to his record 10th French Open.
In Sunday's final, the world number one will face 32nd-ranked Kevin Anderson, the first South African in the championship match in 52 years.
For 2009 champion Del Potro, Friday's match was one too many as the physical and emotional toll of seeing off Roger Federer in four sets in the previous round left him spent.
"I have had an amazing season after some tough moments with injuries in recent years," said Nadal, who started 2017 by finishing runner-up to Federer in Australia.
"It's a very emotional year for me. I am in the final again and get the chance to fight for another title which is very important."
Nadal said the key to Friday's win was a change of tactics after the first set.
"I played too much to his backhand and I felt he was waiting for me there," said Nadal after his 15th successive Grand Slam semi-final win.
"I changed it and it worked very well. I made him move more and make it all more unpredictable."
Nadal finished with 45 winners and 20 unforced errors to Del Potro's 23 and 40.
Despite a 4-0 winning record over Anderson, Nadal said he will not underestimate his opponent on Sunday.
"He is a very dangerous player with a big serve and plays very well on this surface. I have known him since we were 12.
"He's had many injuries but the way he has come back is a great example to the kids."
Del Potro, who saved two match points against Dominic Thiem in a last-16 tie from which he almost retired with illness, gained the only break of the first set in the fifth game off a fortunate net cord.