Juan 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.