Launchbury is one of six changes Lancaster has made from last weekend's 20-14 defeat to Australia, with Alex Corbisiero, Tom Wood and Ben Morgan joining him in a beefed-up forward unit.
Ben Youngs edged the scrum-half debate, reclaiming the shirt from Danny Care, and Mike Brown will start on the wing as England reprise their summer tour tactic of using two full-backs.
Launchbury is seen as England's version of Eben Etzebeth, the 21-year-old South Africa lock singled out this week by coach Heyneke Meyer as one of the Springboks' key hard men.
Etzebeth only made his Test debut against England in June but Meyer, the former Leicester director of rugby, already rates him as one of the world's best second row forwards.
Tellingly, Lancaster did not shy away from the comparisons but he warned England would need more than just Launchbury's power and dynamism if they are to douse the Springbok ferocity.
"I remember watching Etzebeth at the Under-20 World Cup. He has been destined to be a Springbok for a long time. Joe's journey has been different but he is ready for this challenge," Lancaster said.
"You see what he's delivered off the bench against Fiji and Australia, his ability to deal with the international rugby, there's no reason why he shouldn't be an England player for a long time.
"Hopefully we should be sat here in seven or eight years time and I'll be saying 'Joe Launchbury's still the best'.
"But we don't need just one enforcer against the Springboks on Saturday, we need eight.
"We need all our pack to make sure that we are on top of their game to win the breakdown battle, the physical battle, the set piece battle which will be a necessity to win the game."
England, surprisingly, fell short on that front last week. Australia edged the scrum battle for an hour and the Wallabies' flanker Michael Hooper dominated the breakdown contest.
Six changes - including half the forward pack - is a substantial number but Lancaster insisted it was no knee-jerk reaction. A similar number of changes would have been made had England beaten the Wallabies.
Launchbury takes over from Tom Palmer on form but the returns of Corbisiero, Wood and Morgan had all been in the pipeline and they will all add steel to the pack.
The Springbok physicality is nothing new for Launchbury, who spent an eye-opening six-week placement with the Eastern Kings in Port Elizabeth before joining Wasps.
"It's a very big physical game to start my first Test so I understand the responsibility. I do really enjoy that side of the game," Launchbury said.
"As a 19-year-old kid I really learned about the physicality they bring to everything they do. It was huge.
"They are very macho guys and they like to lift heavy weights.
"On my first day I turned up and was told it was live scrums and mauls at 8 o'clock next morning. It was a bit of a culture shock but by the end of the six weeks I was absolutely loving it.
"I believe we are right up there when it comes to physicality too."
For Wood it is a first start since the group stages of the Rugby World Cup after finally overcoming a toe injury and his selection epitomises the "warrior spirit" Lancaster wants in his pack.
Morgan's dynamism in the loose was evident in the Six Nations but he lost his place during the summer tour with Lancaster demanding more from his power game, particularly in defence.
"If you don't match South Africa physically you aren't going to win. You have to win the gainline battle," Lancaster said.
"Ben is a bigger, more physical, more robust number eight in terms of ball carrying (than Waldrom).
"We asked Ben to work on areas defensively to make sure he had an impact in defence. He has worked hard on that and he is chomping at the bit."
The decision to select Brown and Youngs was predicated by the desire to stop South Africa launching their heavy ball-carriers from an attacking platform in England's 22.
Brown, who has replaced Sharples, boasts a strong kicking game and a big left boot, while Care was guilty of a couple of loose kicks from scrum-half last week.
"Our kicking game wasn't as good as it needed to be," Lancaster said.
"This weekend it has to be top notch. If we keep South Africa out of our 22 for long periods, that's going to be important for us.
"Once they get into our 22 they come alive."
Manu Tuilagi and Brad Barritt continue in the centres, meaning Jonathan Joseph returns to the England fold on the bench along with James Haskell and Saracens lock Mouritz Botha.
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