The 29-year-old left-handed opener, who top scored for England with 84 in the second innings of the First Test, will return home for further assessment and treatment at the earliest convenience according to the English Cricket Board.
An ECB statement confirmed that Burns has sustained ligament damage to his left ankle, leaving a major hole in the England line-up after losing the First Test by 107 runs to South Africa.
The Second Test in Cape Town starts on Friday, with 21-year-old opener Zak Crawley expected to replace Burns at the top of the order alongside Dominic Sibley.
Crawley made his Test debut against New Zealand at Hamilton, following an injury to Jos Buttler, but only managed a score of 1 in the match.
England already appear to set to be without Jofra Archer due to an elbow issue, while numerous players were struck down by illness in recent days, including Jack Leach whose been ruled out.
Archer claimed a five-wicket haul in the second innings of the First Test as England bowled out the Proteas for 272.
The 24-year-old Barbados-born quick will remain with the England squad and is expected to be available for the Third and Fourth Tests.
Burns’ injury is likely to lead to a ban on football within the squad, with England director of cricket Ashley Giles known to believe it’s an unnecessary risk of injury.
Jonny Bairstow was injured playing football during the tour of Sri Lanka in 2018.