He was constitutional affairs minister in the last apartheid government and later joined the government of national unity formed in 1994 when Mandela became president.
He left just two years later and went on to co-found the United Democratic Movement. He later became a member of the ANC.
Meyer, a white Afrikaner, was considered a reformist within the NP and was later considered a traitor by some right-wing Afrikaners for his role in the peace talks.
Afrikaners are mostly white descendants of early European settlers and President Trump has said they are currently facing a genocide and persecution in South Africa - a claim that is widely discredited.
This was part of the reason he announced a pause in aid to the country early last year and introduced a policy welcoming Afrikaners as refugees.
Ramaphosa has said it was "completely false" to claim that "people of a certain race or culture are being targeted for persecution".
The news of Meyer's appointment has received a mixed reaction in South Africa, with some calling it a politically savvy appointment and others raising his age as a concern.
The most stinging criticism came from right-wing Afrikaner groups, AfriForum and Solidarity Movement.
AfriForum leader Kallie Kriel, in a post on X, called Meyer an "ANC cadre" whose "history shows that he is someone who is willing to dramatically reposition himself to suit his own personal interests".
Solidarity, which the South African government has accused of peddling misinformation during its visits to the US, said Meyer's appointment was disappointing, especially given his age.
"Far from instilling confidence among Afrikaners, this choice risks deepening existing concerns within our community," the group's spokesperson Jaco Kleynhans said on X.
Meyer had previously addressed the issue of his age when he was questioned about whether he would consider taking up the ambassadorial post if Ramaphosa asked him.
"I don't think somebody of my age should take on that responsibility at this stage quite frankly. [This role] is something that demands everyday, hard work in [Washington] DC ... [and] youthful energy," he said.
Ramaphosa however, defended the appointment, saying Meyer would "represent South Africa very well".
"Meyer is well attuned with the policies of this country," the president told reporters on Wednesday.
Analysts in South Africa have broadly welcomed Meyer's appointment, hailing it as a positive and "clever, tactical decision" by the president.
Dr Oscar van Heerden, a senior research fellow based at the University of Johannesburg, said the selection of a white male Afrikaner flew "in the face of the lie that there is a white genocide" in South Africa.
He also highlighted Meyer's vast experience in government since the apartheid era as a positive, while downplaying concerns raised about his age.
"He still has his wits about him [and has] a set of skills, both in terms of negotiations but also dealing with difficult, intransigent individuals and that will play a part in him interacting with the Trump administration," he told the BBC.
Van Heerden noted that the biggest hurdle facing the South African government is having Meyer's credentials accepted by the US.