"There's about 44 people still speaking it — it's definitely a dying language, it's not a very helpful language," the actress, 47, said this week on US podcast Smartless.
By Thursday, South Africans had taken to Twitter to voice outrage or support.
"Wow what a disrespectful comment to the millions of South Africans of all ages, races...that speak Afrikaans as their first language," said one Twitter user.
"Thank you Charlize Theron - that...racist language is dying and shouldn't even be recognized," said another, in contrast.
One of 11 official languages in South Africa, Afrikaans is commonly used by about 12 per cent of the population of nearly 60 million.
Laws imposing Afrikaans played a role in the oppression of black citizens during the apartheid era, and the language remains controversial in some sectors of society today.
A lawmaker from the opposition leftist Economic Freedom Fighters party tweeted in support of Theron's remarks, but the Freedom Front Plus, a small rightwing and predominantly white Afrikaner party, said she was misguided.
"She is not up to date with what is going on in her country of birth," it said in a statement.
The Hollywood star was born in Benoni, a suburb 40 kilometres east of Johannesburg, and moved to the US almost 30 years ago.
She said she didn't speak English until she was 19 because "nobody" in her predominantly Afrikaans neighbourhood spoke it.
Afrikaans is descended from Dutch spoken by settlers who began to arrive in South Africa in the mid-17th century.
Its centuries-long history in South Africa has sparked debate as to whether it should be considered an indigenous or imported language.
It is the country's third-most spoken language after Zulu, which is used by about 25 per cent of the population, and Xhosa, spoken by nearly 15 per cent, according to official statistics.
In 2020, a court overturned a decision by one of South Africa's largest universities, the University of South Africa, to abolish classes taught in Afrikaans.