Farrell sustained an ankle injury during the 32-15 victory over Australia last Sunday (AEDT) after his Saracens team-mate George was force off with a knee problem.
Eddie Jones has brought Harry Elrington and Jack Singleton into his squad to face the world champions.
Prop Joe Marler will return for international duty on Friday after completing a 10-day isolation following his positive coronavirus test.
Farrell had missed the thrashing of Tonga after the skipper returned a positive COVID-19 test, but started at inside centre in the defeat of the Wallabies.
Jamie Blamire scored his sixth try in only four Tests after coming on to replace George and is poised to start when England do battle with the Springboks.