Del Potro was dominant early, hammering Nadal with his forehand and serving strongly to put the Spaniard in full-defence mode.
"Today was the day to play well", said Nadal, a twice U.S. Open champion. He smiled and waved.
Carreno Busta, the first player to face four qualifiers in any Grand Slam, booked a Friday semi-final against the victor of a night match between South African 28th seed Kevin Anderson and 17th-seeded American Sam Querrey, whose first Slam semi-final in was July at Wimbledon.
He knocked off Federer in the quarterfinals and now is trying to beat them back-to-back for the second time. "I mean, Rafa now is playing within himself a lot".
In the fourth set, Anderson became more aggressive on his forehand and approaching the net.
South Africa's Kevin Anderson overcame a stiff resistance from Spain's P Carrero Busta in the men's singles semis to advance to his maiden grand slam final.
Kevin Anderson savours the moment of reaching his first Grand Slam final. He served 22 aces to one for Carreno Busta, with a fastest serve of 135 miles per hour.
Things got a little hairy in the women's doubles semifinals.More news: Manchester City Call Javier Tebas' 'Peeing in the Pool' Comments 'Pure Fiction'
"But even after the end of the first set, I realized, while I hadn't made too many inroads on his serve games, I played a few points that those were the kind of points that I was looking to play".
The 31-year-old's previous best result in a major competition was reaching the quarter-finals at flushing meadows. After the match, he had an interview where he was nearly like lost for words and that's how we were. Anderson closed the match out on his serve 4-6, 7-4, 6-3, 6-4. Interestingly, it is the first time in Grand Slam history that someone has faced four qualifiers in a row.
Hingis and Murray will face Michael Venus and Chan Hao-Ching in the mixed final.
It's so hard to see Carreno Busta competing with the on-fire serve of Anderson.
It was a string of six straight service holds which followed before Carreno Busta served to stay in the set at 5-6 down.
Anderson finished with a power-packed 22 aces and 58 winners.
While victories over JC Aragone, Ernests Gulbis, Borna Coric and the unsafe Paolo Lorenzi were all high quality, it was the quarter-finals here he really appeared to hit his stride. If he starts strong and gets some momentum, he might be able to take the first set, but that'll be it. He played his typical steady, if unspectacular, brand of tennis, earning two winners against just one unforced error.
It was the first time when Anderson's game was stretched to four sets but the Italian failed to stop Anderson's stunning run at the US Open, losing by 6-4, 6-3, 6-7, 4-6.More news: Florida sheriff bans sex offenders from Hurricane Irma shelters
It's the furthest either man has ever gone in a Grand Slam tournament.
The U.S. Open hasn't had a champion who didn't drop a set since Neale Fraser in 1960.
US ninth seed Williams, the oldest women's entrant at age 37, seeks her third US Open crown after 2000 and 2001. He wouldn't relinquish another game until he owned the second set and a 3-0 lead in the third.
The 4-6 6-0 6-3 6-2 thrashing also moved the Spaniard to the brink of a 16th grand slam title.
The two Lopezes, who are not related, won the 2016 French Open.
Del Potro has been virtually running on empty.
After closing out the match on his serve, Anderson climbed over a flower pot and into the stands to hug his wife, Kelsey, and others in his player's box.
The matches Friday offer quite a contrast in experience and name recognition.More news: Gareth Bale: Ben Woodburn Makes Me Feel Old
A former player at the University of Illinois, Anderson took that chance. "He said:" If he's in the final, he can beat everyone.