The patient was a 30-year-old male from Johannesburg who had no travel history, "meaning that this cannot be attributed to having been acquired outside South Africa," Phaahla told a news conference.
A process of contact tracing was under way, he added.
Monkeypox is a viral disease that causes flu-like symptoms and skin lesions. It is endemic in parts of Africa, but not South Africa.
The World Health Organization will decide on Thursday whether to declare monkeypox a global health emergency. That has stirred criticism from some leading African scientists who say it has been a crisis for some African countries for years.
(Reporting by Alexander Winning and Anait Miridzhanian; Editing by Estelle Shirbon)