Remarkably, it will be Farrell's first senior game of Rugby Union in the number 10 shirt since he switched codes to join Saracens.
Farrell has been promoted to the starting line-up after Olly Barkley was ruled out because of a hip injury.
With Jonny Wilkinson battling to recover from an ankle ligament sprain, England head coach Brian Ashton has taken the decision to go with Farrell.
Barkley, comfortably England's best player against the United States in Lens last Saturday, underwent a scan on Tuesday after being injured in training.
The problem is with his left hip, and England plan to issue a further medical update next Tuesday.
With skipper Phil Vickery sidelined because of a two-match suspension, Leicester flanker Martin Corry will take over as captain against the Springboks.
Matt Stevens moves off the bench to replace Vickery, with Perry Freshwater joining the substitutes.
England have also announced that after careful consideration they will not appeal Vickery's suspension, which means he is ruled out of the pool games against South Africa on Friday and Samoa in Nantes next week.
If, as expected, England lose to South Africa, then they will effectively crash out of the World Cup if they follow that performance up with another defeat against Samoa.
Ashton, meanwhile, has finalised the replacements' bench for the South Africa clash, with Peter Richards joining his fellow scrum-half Andy Gomarsall on the bench, together with Newcastle's Mathew Tait, who has recovered from illness.
England's World Cup campaign is in danger of total melt-down, given the injury and disciplinary problems they have encountered just 10 days after arriving in France.
It is a huge ask for Farrell, whose Union career has been stalled by injury problems, to lead their victory bid against a South African side that is ranked among the tournament favourites.
Ashton could have summoned a replacement from his stand-by list to join the squad, but at this stage both Barkley and Wilkinson are being given more time to prove their fitness ahead of further challenges.