Hooker Jamie George will captain the side in place of the rested Maro Itoje, with England playing a test on South African soil for the first time since 2018.
Fin Smith gets the number 10 jersey ahead of Marcus Smith, who is among the replacements in a 6-2 split between forwards and backs, while wing Immanuel Feyi-Waboso and fullback George Furbank return to the side in a back three that also includes Cadan Murley.
Furbank will play his first test since 2024 as Borthwick brings back several players for what will be an arduous three weekends of travel, during which England will return hom to face Fiji at Everton's Hill Dickenson Stadium in Liverpool, before making the long journey south again to play in Argentina on July 18.
Alex Coles and George Martin make up the lock pairing in Itoje's absence, while the front row contains George and props Ellis Genge and Joe Heyes.
Flankers Ollie Chessum and Tom Curry join number eight Ben Earl in the back row.
"I sense a real excitement within the squad to get our Nations Championship campaign under way,” Borthwick said.
Starting XV: 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 (captain), 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.