"I know that education is the door to freedom," Oprah, clad in an emerald green dress, said at the graduation ceremony.
"So I want to do that for girls who come from backgrounds like my own, who have disadvantaged circumstances but no disadvantaged attitudes or brainpower or spirit. I want to give them the chance that I was given."
Winfrey, 58, told the story of how she mentioned to Nelson Mandela over tea at his house one day that she was interested in building a girls' school in South Africa.
The country's first black president jumped up and immediately called then-education minister Kader Asmal, she said. By that evening Winfrey was in a planning meeting with him.
"I really thought one day I would build a school -- I didn't mean that day," she joked.
Speaking at the idyllic campus of the Oprah Winfrey Leadership Academy for Girls -- which boasts computer and science laboratories, a 600-seat theatre, a 10,000-volume library and even a hair salon -- Winfrey defended the idea of investing lavishly in a small group of promising young women.
The school has faced criticism for focusing on a select few in a country that struggles to meet basic education needs.
"How do you end poverty? This is how you do it," she said at a press conference after the ceremony.
"This is the beginning of the ending of poverty. These girls have now broken the cycle of poverty in their families.
"This model was created specifically to say to South Africa, if you invest in leadership, not just in schools, not just in passing tests, not just in trying to get the exams, but you invest in leadership, then leadership will pay off to your communities and to your nation."
Visibly emotional throughout the ceremony, Winfrey cried as top-10 student Mashadi Kekana gave a commencement speech thanking "Mama Oprah" for her investment in the girls.
But the school has gone through its share of crises to reach this day.
Soon after it opened in 2007, the academy was hit by allegations that a dormitory matron had sexually abused some of the girls. She was arrested and charged, but later acquitted in a decision Winfrey said at the time "profoundly disappointed" her.
Last year, the school was rocked by reports that a dead baby had been found in a student's bag after she apparently hid a pregnancy and gave birth in secret.
But students said the academy had re-shaped their lives.
Livhuwani Rapalalani, 18, who plans to study at Spelman College -- the oldest historically black university for women in the United States -- said Oprah's academy was "totally different" from her public primary school.
"There wasn't much resources, so I wasn't able to grow that much and tap my potential. But when I came here and I had the support and the resources, I was able to grow as a person and actually shine," she told AFP.
"It has wonderful, wonderful facilities, all the resources, all the people you need."
All Saturday's graduates passed their end-of-year exams and will attend universities in South Africa, the United States and other countries.
The campus was packed with celebrating families, journalists and VIP guests, including Mandela's wife, Graca Machel, who gave the keynote address.
Mandela, who is increasingly frail at age 93, did not attend.
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