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Kick-off is at 16:30 SA time.
The 21-year-old Launchbury, who came off the bench against both Fiji and Australia this month, replaced club-mate Tom Palmer, struggling with a calf problem, in a starting side much altered from the one beaten 20-14 by the Wallabies at Twickenham last weekend.
No 8 Ben Morgan, blindside flank Tom Wood and prop Alex Corbisiero, in for injured loosehead Joe Marler, all make their first starts of the European autumn series, with Wood in the XV for the first time since last year's World Cup following a toe injury.
Morgan and Wood replaced Thomas Waldrom, whose failure to ground the ball cost England a try against the Wallabies, and Tom Johnson respectively.
In the backs, Mike Brown, the Harlequins fullback, starts on the left wing with England using two fullbacks - Alex Goode is at No 15 - in a bid to counter the Springboks' expected aerial threat.
Meanwhile Ben Youngs is preferred to Danny Care at scrumhalf.
Ball-playing centre Jonathan Joseph is on the bench with Lancaster opting to continue with the powerful midfield duo of Manu Tuilagi and Brad Barritt despite concerns over England's lack of creativity behind the scrum.
Also among the replacements are versatile loose-forward James Haskell and Saracens lock Mouritz Botha.
England will be looking for their first win over a major southern hemisphere nation under Lancaster having lost twice and drawn once in a three-Test series away to South Africa in June before last week's Wallaby reverse.
"We have picked a team that will give us the best chance of beating South Africa," Lancaster said.
"There were some tight calls, which is what you want as coaches, but the players we have brought in to start have been training well, will bring a real motivation to make the most of their opportunity and will suit the challenge we face against a tough and physical South African team."
Springboks coach Heyneke Meyer named on Wednesday a starting XV unchanged from the one that beat Scotland 21-10 at Murrayfield last weekend.
Lancaster's men conclude their European autumn campaign against world champions New Zealand at Twickenham on December 1.
Teams:
England:
15 Alex Goode, 14 Chris Ashton, 13 Manusamoa Tuilagi, 12 Brad Barritt, 11 Mike Brown, 10 Toby Flood, 9 Ben Youngs, 7 Chris Robshaw (captain), 6 Tom Wood , 5 Geoff Parling, 4 Joe Launchbury, 3 Dan Cole, 2 Tom Youngs, 1 Alex Corbisiero
Substitutes: 16 David Paice, 17 David Wilson, 18 Mako Vunipola, 19 Mouritz Botha, 20 James Haskell , 21 Danny Care, 22 Owen Farrell, 23 Jonathan Joseph
South Africa:
15 Zane Kirchner, 14 JP Pietersen, 13 Juan de Jongh, 12 Jean de Villiers (captain), 11 Francois Hougaard, 10 Pat Lambie, 9 Ruan Pienaar, 8 Duane Vermeulen, 7 Willem Alberts, 6 Francois Louw, 5 Juandré Kruger, 4 Eben Etzebeth, 3 Jannie du Plessis, 2 Adriaan Strauss, 1 Gurthrö Steenkamp
Substitutes: 16. Schalk Brits, 17 Heinke van der Merwe, 18 Pat Cilliers, 19 Flip van der Merwe, 20 Marcell Coetzee, 21 Elton Jantjies, 22 Jaco Taute, 23 Lwazi Mvovo
