World number one Nadal faces big-serving Argentine third seed Juan Martin del Potro while sixth seed Novak Djokovic meets Japanese 21st seed Kei Nishikori bidding to secure a seventh trip to the showcase match at Flushing Meadows.
Nadal, who survived a gruelling late-night battle with Austrian Dominic Thiem in punishing humidity to reach the last four, has a commanding 11-5 career record against Del Potro with his last loss coming in the semis at the 2016 Rio Olympics.
The Spaniard, who beat Del Potro this year in the French Open semi-finals and Wimbledon quarter-finals, has looked nothing short of brilliant but is not about to get ahead of himself as the pair have split their 10 meetings on hard courts.
"He (Del Potro) is a great player everywhere. But the challenge of playing him on hard (courts) of course is even higher for me personally than playing against him on clay," said Nadal, who has three U.S. Opens among his 17 Grand Slam titles.
"It will be a big challenge. It's a match in which we know each other very well. I know he's playing well. I know I'll have to play at my highest level to keep having chances of success."
Del Potro will rely heavily on his service having won 83 percent of his first service points through five matches here, well above anyone else remaining in the men's draw.
In Friday's other semi-final, Djokovic will try to extend the form that has seen him win 24 of his last 26 matches, an impressive run that includes titles at Wimbledon and the U.S. Open tune-up event in Cincinnati.
He has a 14-2 record against Nishikori, whose last victory over the Serb came in the 2014 U.S. Open semi-finals before he lost in the showpiece match to Croatian Marin Cilic, who the Japanese overcame in five sets to reach this year's last four.
Djokovic, who beat Nishikori in the Wimbledon quarters, said he expected a tough match against an opponent with a lethal two-handed backhand who is one of the fastest players on tour.
"I can't really say he's a great match-up for me," said the Serb. "I have a very good head-to-head score against him. But because he plays so fast he makes me more alert from the first point because I know I have to be at my best in order to compete with him from the baseline."
(Reporting by Frank Pingue; Editing by Ken Ferris)
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