uan Martin del Potro will try to extend his thrilling US Open run all the way to the final when he faces top seed Rafael Nadal in the last four.
The Argentine 24th seed came back from two sets down to beat Dominic Thiem in round four and beat five-time champion Roger Federer in the quarter-finals.
Del Potro and Nadal meet in Friday’s second semi-final at about 23:30 BST.
Spain’s Pablo Carreno Busta and Kevin Anderson of South Africa open play at 21:00.
The pair will make their Grand Slam semi-final debuts after excelling in the bottom half of the draw, which lost British second seed Andy Murray to injury before the tournament started.
‘Sport is not that difficult’
Del Potro has been the story of the second week in the men’s draw with his miraculous comeback against Thiem followed by a brilliant win over Federer.
However, the 28-year-old has spent 13 hours and 20 minutes on court – one hour and 40 minutes more than Nadal – and admitted: “Physically I’m not in the perfect conditions, but when you play semi-finals on the Grand Slam, everything can happen.
“So you must be ready for the chance and playing against Rafa in my favourite tournament, I will try to enjoy the atmosphere, the game, and I know if I play my best tennis, I could be a danger for him.”
Asked about the huge forehand which has brought him 69 winners already, he added with a smile: “He’s a lefty guy, so he has chance to find easily my backhand.
“So I don’t know what’s going to be my strategy for that match.
“But for sure I will try to make winners with my forehands and don’t run too much, because my legs are tired.”
Nadal, 31, is looking to end the Grand Slam season with his second major of the year and 16th overall, and his form has steadily improved in New York.
“Sport is not that difficult,” said the Spaniard. “The player who plays better that day is the player that is going to have better chances.
“Then there are small adjustments, if you can do it, yes. But the most important thing is to play at my best level.
“If I play at my best level, I believe I’m going to have my chances against everybody.”
‘You have to do your best to take advantage’
Fourth seed Alexander Zverev, fifth seed Marin Cilic and eighth seed Jo-Wilfried Tsonga were among the leading names to lose early, and the less heralded Carreno Busta and Anderson have taken full advantage.
Carreno Busta, seeded 12th, played qualifiers in his first four matches and then beat 29th seed Diego Schwartzman, reaching the semis without dropping a set.
“Of course I know that I have a good draw here,” said the Spaniard.
“I play against qualifiers in first, second, third and fourth round. That’s true that Denis [Shapovalov] was really tough. He’s not a normal qualifier.
“But when you have this draw, you have to do your best to take advantage, so I think that is a really good tournament for me.
“I know that I didn’t win matches against top players, top-10 or top-20 players, but I am very happy with my tournament.”
Anderson, the 28th seed, played some of the best tennis of his career as he knocked out in-form American Sam Querrey in the last eight.
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.
“I feel like that’s something I have sort of added to my game,” he said.
“You know, those matches are tough. I feel like I just try to play each point as best as I can.”