"We are looking for ways to enhance and deepen our partnership. South Africa has so much to offer to the rest of the world," Clinton said as she met with Nkoana-Mashabane.
While the two countries almost always have similar objectives on international situations, they often differ on the path to take to achieve desired results, she said.
"As crises and opportunities arise, there are tough issues we have to tackle together, from nuclear proliferation to climate change, security crises, the situation in Democratic Republic of Congo (DRC) or Syria.
"We do not always see eye-to-eye on these issues. I don't know if people always do and certainly not two nations. Sometimes we will disagree as friends do," she said.
A senior state department official said Clinton wants to "encourage South Africa to play a stronger and more influential role" in global affairs.
South Africa, currently a non-permanent member of the UN Security Council, last month abstained from a heated vote on sanctions against Syria backed by European nations and the US.
South Africa said it wanted a more balanced approach and measures to prod the rebels to comply with the proposed peace plan.
But a senior US diplomat said while in agreement with South Africa's concerns, "we don't think it's a parallel situation. The [Syrian] government is using military planes … so there's a slight difference on that."
South Africa's preference for longer negotiations to approach conflicts can be attributed to its historical background, the diplomat said.
And the country "gets very nervous when words like regime change get mentioned. We are not nervous about those words," said the diplomat.
Outside the differences in tactics, "fundamentally the US and South Africa share the same values," said the state department official.
"Strategic dialogue with the minister is the linchpin of the trip," a senior US diplomat said.
Nkoana-Mashabane said the Southern African country "regards US as an important player in the context of north-south relations."
"I believe as partners on the continent we can do more about stability and the ways we are going to foster security, economic growth and development."
She thanked Clinton for her "personal commitment to elevate this relationship".
Clinton is later set to hold talks with the newly elected chairperson of the African Union Commission, South Africa's Nkosazana Dlamini-Zuma.
Dlamini-Zuma recently said she was opposed to the arrest of Sudanese President Omar al-Bashir, who is wanted by the International Criminal Court on genocide charges, because his involvement in peace talks was needed. – Sapa-AFP