The sanctions were placed under the US Global Magnitsky Act which targets large-scale corruption and human rights violation.
"Today's sanctions announcement demonstrates the US government's unwavering commitment to supporting the rule of law and accountability in South Africa," the Treasury said.
The US Treasury announced sanctions Thursday on South Africa's Gupta family and associate Salim Essa, calling them a "significant corruption network" that dispersed bribes and misappropriated millions in state funds.
The wealthy, Indian-born Guptas are at the centre of a judicial inquiry into rampant corruption during the nine-year administration of South Africa's former president Jacob Zuma.
"The Gupta family leveraged its political connections to engage in widespread corruption and bribery, capture government contracts, and misappropriate state assets," said Sigal Mandelker, Treasury under secretary for terrorism and financial intelligence.
"Treasury's designation targets the Guptas' pay-to-play political patronage, which was orchestrated at the expense of the South African people," she said.