She died peacefully in the hospital after a long illness, according to her family.
While Mandela was held at the Robben Island penal settlement, off Cape Town, where he spent most of his 27 years in jail, Madikizela-Mandela acted as the main conduit to his followers.
During her almost 38-year marriage to Nelson Mandela, she fought for black majority rule even as she vowed to escape the shadow of the great man.
A longtime stalwart of the ruling African National Congress, or ANC, political party, Madikizela-Mandela was a member of South Africa's parliament at the time of her death. Winnie joined the struggle against apartheid led by Mandela, she even worked as a hospital worker in the 1950s.
Additional reporting from Newsy affiliate CNN. This is a woman the nation of South African was honoured to call Mother of the Nation.
In 2011, Madikizela-Mandela was the subject of a Hollywood biopic starring Oscar-winning actress Jennifer Hudson, along with an opera that premiered in Pretoria, South Africa. She bore the air of a troublemaker, arriving late at rallies and haranguing comrades, including Thabo Mbeki, Mandela's successor as president.
Mandela, approaching 40 and the father of three, declared on their first date that he would marry her.
The couple divorced in 1996, two years after Mandela became president in South Africa's first all-race elections, with Mandela accusing his wife of infidelity.
She denied the allegations but was found guilty of kidnapping and sentenced to six years imprisonment. And when they eventually married, it was clear that the man she loved, loved politics and his country above all else, but she grew to understand this-difficult as it was.
Ms Madikizela-Mandela will be honoured by a state funeral on April 14, preceded by an official memorial service on April 11, said President Cyril Ramaphosa after visiting her home in Johannesburg's Soweto township on Monday evening.
South Africa's Truth and Reconciliation Commission also accused her of human rights abuses during the apartheid years.
Ms Madikizela-Mandela always was aware of the danger of being overshadowed by her husband's all-encompassing personality, and she vowed not to lose herself. "May she forever rest in #Power".
"'She dedicated most of her adult life to the cause of the people, and for this was known far and wide as the Mother of the Nation, '" reports NBC News of the family's statement.
She remained steadfast and unbowed throughout, emerging to punch the air triumphantly in the clenched-fist salute of black power as she walked hand-in-hand with Mandela out of Cape Town's Victor Vester prison on February 11, 1990. As she saw it, her role was to stiffen the confrontation with the authorities.
After blacks rioted in the segregated Johannesburg township of Soweto in 1976, Madikizela-Mandela was again imprisoned without trial, this time for five months.
"And he shed tears to say that "we have chose to separate".