Frances Tiafoe will aim to become the first American man to reach the US Open final since 2006 when he plays Carlos Alcaraz in the last four in New York.
Casper Ruud, of Norway, plays Russian Karen Khachanov in Friday's first semi-final at Flushing Meadows (20:00 BST).
A first-time Grand Slam champion is guaranteed in the men's singles.
It is also the first time there have been four new men's semi-finalists at the US Open since the inaugural tournament in 1881.
Spain's Alcaraz, 19, and 23-year-old Ruud have a chance of becoming the world number one if they reach the final.
Alcaraz faces Tiafoe on Arthur Ashe Stadium at 00:00 BST.
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