Health Minister Joe Phaahla said on Thursday that he had been notified by the country's laboratory services that they had confirmed the first monkeypox case in South Africa.
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.