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.
Anderson reached his maiden final at the majors by beating 12th-seeded Pablo Carreno Busta of Spain 4-6, 7-5, 6- 3, 6-4.
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 of a fortunate net cord.
However, few would begrudge Del Potro a little luck after he was pushed to the brink of retirement by four wrist surgeries that saw his ranking slip as low as 1,045 and forced him to miss 10 Grand Slam tournaments.
Nadal hit back with venom, gathering three breaks to take the second set in just 26 minutes as the Argentine suffered a power cut of staggering proportions.
The Spaniard, watched by Tiger Woods in his player's box, then raced into a 3-0 lead in the third before Del Potro stopped the rot, having lost nine games in succession.
The Argentine saved two set points in the eighth game but Nadal soon wrapped it up at the next time of asking, pushing his opponent into desperate defence before the delivering the killer blow into an open court.
Nadal, beaten by Del Potro at the same stage in 2009, tightened the noose with two breaks for 4-1 and easy hold for 5-1.
It was all over in the eighth game when Nadal buried unleashed a backhand winner.
"I'm angry to lose a chance like this, but maybe tomorrow I will be calm and see how big the tournament was for me," said Del Potro.
Anderson, 31, will attempt to become his country's first Slam champion since Johan Kriek at the 1981 Australian Open.
Cliff Drysdale was the last South African man in the US final in 1965 but he was defeated by Manuel Santana.
"It has been a long road. This means the world to me," said Anderson, whose career was at a crossroads in January when hip problems forced him out of the Australian Open and his ranking slumped to 80.
"This is why we work so hard. I was pretty nervous with it being the first time on the sport's most famous stage."
Carreno Busta, also playing in his first semi-final at the Slams, had not dropped a set at the tournament, helped by playing four qualifiers, and he was a set to the good on Friday, breaking in the seventh game.
The Spaniard had pocketed the opener hitting just two winners and only one unforced error.
But 6ft 8in (2.03m) Anderson eventually imposed himself much to the approval of watching Hollywood star Robert Redford and Microsoft founder Bill Gates
Anderson finished the tie with a power-packed 22 aces and 58 winners.
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