The 22-year-old will have an operation in Cape Town on Monday, just over a week after he was named one of the five nominees for the International Rugby Board (IRB) World Player of the Year Award for 2013.
"At this point in time, the specialist's assessment is that Etzebeth will be out of action for a minimum of 16 to 18 weeks," said a statement from the Stormers, his Super Rugby team.
"It's very unfortunate to again start a new season without Etzebeth," coach Allister Coetzee added.
Etzebeth also missed the start of last season after injuring an ankle in a pre-season match.
The Stormers recently signed Argentine lock Manuel Carizza, who arrives in Cape Town in January.