Nadal came from a set down to beat Diego Schwartzman in the last-eight and now faces fifth seed Del Potro.
The Argentinian has beaten Nadal on five occasions, though lost both encounters the pair have fought on clay.
Their last meeting came at last year’s US Open with Nadal prevailing in the semi-finals in four sets.
Del Potro beat Marin Cilic in four sets in his quarter-final and Nadal is expecting a tough test on Friday.
“Del Potro has achieved great victories this year,” Nadal said.
“He has fantastic potential. Aggressive game from the end of the court, the baseline.
“And I have to play aggressively. If I play defensively and I don’t take intensity, I will lose.”
That match closes proceedings on Philippe-Chatrier with the other men’s semi-final between Novak Djokovic’s conquerer Marco Cecchinato and Dominic Thiem first up
Friday’s French Open order of play
Play starts at 1pm
Marco CECCHINATO (ITA) vs Dominic THIEM (AUT)
Not before 3.30pm
Rafael NADAL (ESP)  vs Juan Martin DEL POTRO (ARG) 
Play starts at 11am
Mansour BAHRAMI (FRA) & Fabrice SANTORO (FRA) vs Arnaud BOETSCH (FRA) & Pat CASH (AUS)
Not before 12:30pm
Feliciano LOPEZ (ESP) & Marc LOPEZ (ESP)  vs Oliver MARACH (AUT) & Mate PAVIC (CRO) 
Eri HOZUMI (JPN) & Makoto NINOMIYA (JPN) vs Hao-Ching CHAN (TPE) & Zhaoxuan YANG (CHN) 
Barbora KREJCIKOVA (CZE) & Katerina SINIAKOVA (CZE)  vs Andrea SESTINI HLAVACKOVA (CZE) & Barbora STRYCOVA (CZE)