The 85-year-old had been diagnosed with cancer earlier this year.
He came to power in 1989 under apartheid, a system of legalised racism, but later became a key figure in the transition to democracy.
He ordered Nelson Mandela's release from prison, leading to historic polls where the anti-apartheid leader became the first black president.
De Klerk shared the Nobel Peace Prize with Mandela for helping to negotiate an end to apartheid. But his legacy divides opinion in South Africa.