Handre Pollard is set to miss the Super Rugby season, South Africa's Test series against Ireland and the Rugby Championship after rupturing knee ligaments in training.
The fly-half will undergo surgery on Wednesday and could be out for up to nine months, his club the Bulls announced on Tuesday.
"Handre was easing back into training, his first phase of final rehab before being cleared to play and was busy with a passing drill when he injured himself," coach Nollis Marais said in a statement. "This is pretty devastating for all of us as Handre was a key player for us."
Pollard was taking part in fitness tests with the Pretoria-based Bulls after returning from Japan, where he had been playing for NTT Docomo Red Hurricanes on a short-term contract.
The 21-year-old has earned 20 caps for the Springboks since making his debut in 2014 and was a key performer in their third-place finish at last year's World Cup.
Pollard has recently extended his contract with the Bulls until 2019, but was allowed to play in Japan for three months after the World Cup. The Bulls' Super Rugby campaign kicks off against the Stormers on February 27.