Khumalo, on loan from Tottenham, faces six months out after seriously damaging his kneecap during his country's 5-0 defeat to Brazil in Johannesburg on Wednesday night.
The 27-year-old's agent Glyn Binkin said: "Bongani will be having an operation early this afternoon (Thursday), but he will likely be out for a lengthy period. Six months or so.
"Bongani is honestly the strongest player mentally that I've ever worked with. He has overcome many massive hurdles in his career to date and sees this as yet another one to overcome.
"He is very upbeat and confident that he will bounce back even stronger."
Khumalo has made 32 appearances for Doncaster since arriving at the Sky Bet Championship club in the summer.
His injury setback comes just a week after skipper, and fellow central defender, Rob Jones was also ruled for the rest of the season with a neck problem.