Harlequins full-back Mike Brown, Gloucester prop Nick Wood and Sale Sharks lock Dean Schofield will make their debuts.
Brown only made his first team bow for Quins last season, while Wood and Schofield are also rewarded for impressive campaigns with their clubs.
England have travelled to South Africa with a severely-depleted squad and that level of inexperience is inevitably reflected in Ashton's line-up, which has a total of 172 caps.
But 131 of those are shared by just three players - skipper Jason Robinson, fly-half Jonny Wilkinson and hooker Mark Regan.
Regan will pack down in the front row with his fellow 35-year-old, Sale prop Stuart Turner, with Regan making his first Test appearance since the 51-15 defeat against Australia in Brisbane almost three years ago.
There are just three survivors from England's last game, the RBS Six Nations Championship defeat against Wales in Cardiff - Robinson, fellow wing David Strettle and centre Mathew Tait.
Saracens centre Andy Farrell is recalled to partner Tait in midfield after recovering from a back problem, while Peter Richards has beaten off the challenges of scrum-half rivals Andy Gomarsall and Shaun Perry to wear the number nine shirt.
In the forwards, Ashton has focused on players who have made a mark for their clubs in recent months, with Wood joined in the pack by his Gloucester colleagues Alex Brown and Andy Hazell.
Flanker Hazell has been one of the Guinness Premiership's dominant figures this term, and he will win his seventh cap in the back row with Chris Jones at blindside flanker and Nick Easter at number eight.
There are also three uncapped players on the bench - Saracens hooker Matt Cairns, together with Bristol forwards Darren Crompton and Roy Winters - but Gomarsall, Worcester flanker Pat Sanderson and Gloucester back Iain Balshaw provide plenty of experience in reserve.
Saracens forward Ben Skirving is the solitary player among seven uncapped squad members who does not feature in the Test 22.
England, who will face South Africa in a crucial World Cup pool clash in Paris on September 14, are not expected to trouble the Springboks during the next fortnight.
Springboks coach Jake White plans to announce his team tomorrow, and it should be an infinitely stronger line-up than the one Ashton is able to parade.
England have not won away from home since February last year, losing six successive Tests on the road against Scotland, France, Australia (twice), Ireland and Wales, and it is highly unlikely that sequence will be ended either in Bloemfontein or Pretoria on Saturday week.