Elected by the 54-member pan-African bloc in Ethiopia on Sunday, she becomes the first woman to head the African Union commission.
An experienced diplomat, Dlamini-Zuma (63) is known for her competent management and stern personality.
A doctor by training, she was health minister when Mandela became the country's first black leader.
She went on to be foreign minister for a decade, earning praise for her shuttle diplomacy to end the war in the Democratic Republic of Congo.
But her critics found fault with her "quiet diplomacy" towards neighbour Zimbabwe, during a crisis that saw President Robert Mugabe evict thousands of white farmers from their land in 2000.
Her former husband President Jacob Zuma named her interior minister.
Although that was seen as a demotion, she won plaudits for turning around a ministry mired in gross mismanagement to achieve the first clean audit in 16 years.
'I'm a Zulu'
In her campaign to win the pan-African bloc's top job, she vowed to work at making it "a more efficient and effective organisation".
And while she may have defeated the incumbent, French-speaker Jean Ping of Gabon, she has refused to be labelled as an English-speaking candidate.
"I am not Anglophone, I'm Zulu," she said.
Once she got to work in the post, she added, she would be "implementing programmes … agreed upon by everybody" rather than "consulting the Anglophone and the Francophone".
Dlamini-Zuma has the backing of the predominantly English-speaking Southern African region and is the first person from the region to hold the top commission job since the AU was created a decade ago.
"She takes her work very seriously," said Prince Mashele, an analyst at the Centre for Politics and Research, who worked with Dlamini-Zuma's ministry when she was foreign minister. "She has the rare quality of putting up very good administrators," Mashele added.
'A little more affable'
But she has raised eyebrows with her unsmiling demeanour.
"I thought she could do better if she was a little more affable," said Mashele.
Born January 27 1949, in the eastern province of KwaZulu-Natal, Dlamini-Zuma took up politics in high school.
In the 1970s she went into exile, and studied in Britain at the universities of Bristol and Liverpool, while helping organise the anti-apartheid movement overseas.
She met Zuma while working as a paediatrician at a Swaziland hospital and became the polygamist president's third wife in 1982. They divorced in 1998.
When the ban on the ANC was lifted in 1990, she returned home.
After the first democratic elections she was tapped by Mandela to transform the country's segregated health system.
She is remembered for introducing legislation that overhauled the highly unequal system and gave the poor access to free basic care.
But she was also criticised for championing a controversial HIV drug that was later proved to be ineffective.
When Zuma fell out with ex-president Thabo Mbeki and moved to oust him as ANC leader in 2007, she stood as Mbeki's running mate for the ANC presidency.
But when Zuma won party polls and later become president, he kept his ex-wife in his Cabinet – a rare Mbeki ally to avoid the axe.
"She is an astute politician, a veteran, the experience she acquired as foreign minister puts her in good stead to take over this role" at the AU, said Keith Gottschalk of the University of the Western Cape. – AFP