Jamie George captains the side, with Ollie Chessum and Ellis Genge serving as vice-captains. The match marks England's opening fixture in the inaugural Nations Championship, with matches against Fiji and Argentina to follow in the coming weeks.
"Playing South Africa at Ellis Park is one of the great tests in world rugby and an opportunity we're excited to embrace," said Borthwick.
"We've prepared well since we arrived here last week and I sense a real excitement within the squad to get our Nations Championship campaign underway."
Following the match in Johannesburg, England return for an 'away' fixture against Fiji at Everton's Hill Dickinson Stadium in Liverpool before travelling to Argentina to face Los Pumas at Estadio Unico Madre de Ciudades, Santiago del Estero in Round 3.
England - 15 George Furbank, 14 Immanuel Feyi-Waboso, 13 Tommy Freeman, 12 Seb Atkinson, 11 Cadan Murley, 10 Fin Smith, 9 Jack van Poortvliet, 8 Ben Earl, 7 Tom Curry, 6 Ollie Chessum, 5 George Martin, 4 Alex Coles, 3 Joe Heyes, 2 Jamie George (c), 1 Ellis Genge.
Replacements: 16 Luke Cowan-Dickie,17 Beno Obano, 18 Asher Opoku-Fordjour, 19 Charlie Ewels, 20 Guy Pepper, 21 Henry Pollock, 22 Alex Mitchell, 23 Marcus Smith.
Australia's Ben Donaldson missed a late penalty as Ireland narrowly beat the hosts 33-31 in their Nations Championship encounter at the Allianz Stadium in Sydney on Saturday.
New Zealand beat France 34-32 in a keenly contested Nations Championship clash in Christchurch on Saturday as Dave Rennie's tenure as head coach kicked off with a win.
England's preparations for their World Cup Round of 16 clash with tournament co-hosts Mexico have been marred by logistical uncertainty and a hostile reception.
Springbok captain Siya Kolisi said South Africa are taking nothing for granted ahead of Saturday's Nations Championship opener against England.
