The 31-year-old Spaniard, the 2010 and 2013 champion in NY, will be playing in his 23rd Slam final and third this year, looking to add the USA title to his record 10th French Open.
World No.1 Nadal will be the heavy favourite on Sunday against No.32 Anderson, who beat Pablo Carreno Busta 4-6 7-5 6-3 6-4 to become the lowest-ranked US Open finalist since the ATP's computer rankings began in 1973.
"It's been an wonderful season, of course, after a couple of years with some troubles, injuries, tough moments", Nadal said.
"In some ways I'm actually happy I made the quarters, so I'm not disappointed, because it's been a good run this year already". But the most important thing is to play at my best level.
"After the first set I changed it a little bit, changed my tactic, strategy a little bit".
Nadal stressed the importance of reaching the final of the last Grand Slam of the season, which he considers the most important match of the season.
Del Potro was dominant early, hammering Nadal with his forehand and serving strongly to put the Spaniard in full-defence mode.
Looking forward to his next opponent, Nadal said: "It will be very tough against Kevin".
"I been exhausted after Thiem match, Roger match", said the 2009 USA open champ.More news: Brock Osweiler passes physical, returns to Denver Broncos
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"He has an unbelievable serve and is a great example for the kids in the way he has come back from injury".
He quickly found his rhythm and produced a comeback to win the match 4-6 6-0 6-3 6-2 in two hours and 30 minutes.
Carreno Busta, 12th head of the series, was also competing in his first semi-final of a major tournament in his career and had not conceded any round before facing Anderson.
Del Potro exhausted at the end of a strenuous week, but Nadal would have broken the spirit of most men. He only had to cover 60% of the court most of the time, no?
Nadal holds a 8-5 career record against the Argentine; he won their first four meetings, but del Potro has a 5-4 edge in the past nine matchups.
It was all over in the eighth game when Nadal buried unleashed a backhand victor.
"I think he (Nadal) just played better than me".
At 6ft 8in tall, Anderson's game has always been built around a big serve - he leads the tournament with 92 aces - but the affable South African has been working on a more aggressive attitude.
"It's been a long road".
"To be honest, I'm angry to lose a chance like this, but maybe tomorrow, after tomorrow, I will be calm and see how big the tournament was for me", said Del Potro after his 4-6, 6-0, 6-3, 6-2 loss to the world number one.