Cipriani has had a three-year absence form the national team and he joins seven uncapped players on the tour.
Brad Shields, Ben Earl, Ben Spencer, Dan Robson, Jack Willis, Jonny Hill and Cameron Redpath are all given their first shot to showcase their talents on the international stage.
Owen Farrell has been named captain while hooker Dylan Hartley is unavailable.
And England head coach Eddie Jones is hoping the newcomers will grab the opportunity with both hands.
“Our tour to South Africa will be the most exciting challenge for us as a group since 2016,” Jones said.
“We have an opportunity to create some history next month and win the Test series, something no England side has done before.
“There are a number of players out injured or not selected so it provides a big opportunity for others.
“With three weeks to prepare for the first Test in Johannesburg I am expecting players to come into camp with the right mind-set and we will be looking for them to break the mould in terms of being more assertive and on the front foot in everything we do.
“We will need to be physically aggressive and tactically smart against the Springboks who we know will be combative and reinvigorated by their new coaching setup.”
England squad to tour South Africa:
Backs: Mike Brown (Harlequins), Elliot Daly (Wasps), Nathan Earle (Saracens)*, Jonny May (Leicester Tigers), Denny Solomona (Sale Sharks), Danny Cipriani (Wasps), OwenFarrell (Saracens), George Ford (Leicester Tigers), Alex Lozowski (Saracens), Cameron Redpath (Sale Sharks)*, Dan Robson (Wasps)*, Henry Slade (Exeter Chiefs), Ben Spencer (Saracens)*, Ben Te’o (Worcester Warriors), Ben Youngs (Leicester Tigers)
Forwards: Tom Curry (Sale Sharks), Ben Earl (Saracens)*, Jonny Hill (Exeter Chiefs)*, Nick Isiekwe (Saracens), Maro Itoje (Saracens), Joe Launchbury (Wasps), Chris Robshaw (Harlequins), Brad Shields (Hurricanes/Wasps)*, Sam Simmonds (Exeter Chiefs), Billy Vunipola (Saracens), Jack Willis (Wasps)*, Mark Wilson (Newcastle), Luke Cowan-Dickie (Exeter Chiefs), Ellis Genge (Leicester Tigers), Jamie George (Saracens), Joe Marler (Harlequins), Kyle Sinckler (Harlequins), Mako Vunipola (Saracens), Harry Williams (Exeter Chiefs)
Not considered for selection:
Backs: Danny Care (Harlequins), Jonathan Joseph (Bath Rugby), Harry Mallinder (Northampton Saints), Joe Marchant (Harlequins), Jack Nowell (Exeter Chiefs), Semesa Rokoduguni (Bath Rugby), Manu Tuilagi (Leicester Tigers), Anthony Watson (Bath Rugby), Richard Wigglesworth (Saracens)
Forwards: Jack Clifford (Harlequins), Dan Cole (Leicester Tigers), Tom Dunn (Bath Rugby), Charlie Ewels (Bath Rugby), Dylan Hartley (Northampton Saints), James Haskell (Wasps), Nathan Hughes (Wasps), George Kruis (Saracens), Courtney Lawes (Northampton Saints), Will Spencer (Worcester Warriors), Sam Underhill (Bath Rugby)