"We have been tasked by our respective presidents, the [South African] foreign minister and I, to put meat on the bone, to get to work, to make sure the expectations of President Zuma and President Obama are met," she said.
Relations between the US and Africa's largest economy struggled under the administrations of George Bush, Obama's predecessor, and Thabo Mbeki, his South African counterpart, due to differences over Iraq, the fights against Aids and the situation in Zimbabwe.
The US secretary of state is on an 11-day tour of Africa.
On Friday, Clinton urged South Africa must push neighbouring Zimbabwe to undertake political, social and economic reforms.
"South Africa is very aware of the challenges posed by the political crisis in Zimbabwe because South Africa has three million refugees from Zimbabwe," she said on Friday after talks with Maite Nkoana-Mashabane, the foreign minister.
Lindiwe Zulu, an adviser to Zuma, told Al Jazeera that the president was keen to see reforms implemented in Zimbabwe.
"[Zuma] is very prepared to engage as far as he can in order to resolve the problems and the challenges that are faced by the Zimbabwean people, because every negative thing that happens in Zimbabwe has a direct impact on South Africa."
Washington has maintained sanctions against Robert Mugabe, the Zimbabwean president and his closest aides, despite the implementation of a coalition government with the former opposition.