Lancaster has made a brave positional switch for the Durban clash by pushing full-back Ben Foden out to the left wing and bringing in Mike Brown at number 15. Lancaster believes having two full-backs on the field will improve the team's defences under high balls while both players also offer an adept kicking game.
"Mike has had an outstanding season," Lancaster said.
"He brings a left-footed kicking game and great aerial skills along with Ben. Ben is obviously a great strike runner as well. He has been great about it and he can see the benefits of how this can open his game up."
He added: "When you make these decisions there is an element that wonders how he will go in this situation but we have had 10 days together, and we have worked on it for those 10 days.
"Sometimes you have to make brave decisions and, from my point of view, it is the right decision for the team and it is going to benefit the team massively, hopefully."
The pair will form a back three with right winger Chris Ashton, who played full-back in his rugby league days with Wigan.
"It is a great opportunity to see them together and, if training is anything to go by, we should be excited by those combinations," Lancaster said.
The England team for the series opener at Kings Park contains three other changes from the side which beat Ireland in the final RBS 6 Nations match in March.
Harlequins prop Joe Marler and Exeter flanker Tom Johnson come in for their debuts while Ben Youngs is preferred at scrum-half to Lee Dickson.
Marler has a reputation for hot-headedness and, supporting a Mohican, is one of the game's colourful characters but Lancaster has no disciplinary concerns.
He said: "I think he has matured massively during the last 12 months.
"All the players recognise discipline is going to be a key factor on Saturday - we can ill afford to give away penalties - and I think Joe has been excellent throughout the season."