Mrs Clinton will hold meetings with her South African counterpart and with former President Nelson Mandela on the first of three days in the country.
Talks will focus on business and on HIV/Aids, which affects nearly 6 million South Africans.
In the coming days she will meet President Jacob Zuma, for talks likely to include the situation in Zimbabwe.
Correspondents say Mrs Clinton will ask Mr Zuma to use his influence to combat what she has called "negative effects of the continuing presidency of President [Robert] Mugabe" in Zimbabwe.
Relations between the US and South Africa were warm during the 1990s under Presidents Mandela and Bill Clinton, says the BBC's Jonah Fisher in Johannesburg.
A commission was established to prioritise areas of co-operation but when Mr Clinton left the White House this was quietly forgotten.
South African officials hope that the visit by Mrs Clinton, the former US president's wife, will signal a new period of cooperation, says our correspondent.
On Friday morning, Mrs Clinton is holding talks with South African Foreign Minister Nkoana-Mashabane and Deputy President Kgalema Motlanthe.
Later, she will meet Mr Mandela, South Africa's first black president, and attend a conference with Health Minister Aaron Motsoaledi before travelling to the South African capital Pretoria for National Women's Day events.