Harlequins fly-half Marcus Smith will make his eagerly awaited England debut, with Gloucester’s Lewis Ludlow captain against the United States on Sunday.
The pair are among eight uncapped players in the starting XV, with 11 England internationals in South Africa with the British and Irish Lions.
Head coach Eddie Jones says the game at Twickenham is a chance for players to “make their mark with England”.
Prop Ellis Genge will be vice-captain and Sam Underhill starts at flanker.
Underhill missed the 2021 Six Nations because of a hip injury but returns alongside Ludlow and uncapped Newcastle number eight Callum Chick in the back row.
Two years out from the next World Cup, Jones is building a side for the future while so many of his senior players are absent.
Bristol scrum-half Harry Randall also makes his England debut, while Wasps fly-half Jacob Umaga awaits his first international cap on the bench.
Sale hooker Curtis Langdon and Leicester prop Joe Heyes join Genge as they make their first appearances in an England front row.
Josh McNally makes his international debut in the second row alongside Bath team-mate Charlie Ewels.
Outside centre Henry Slade is the most capped player in the side with 38 caps and is alongside Ollie Lawrence at 12.
Max Malins – who has started for Jones once before at full-back – is on the left wing, while on the right Joe Cokanasiga makes his first England appearance since playing against the United States at the 2019 Rugby World Cup.
Leicester’s Freddie Steward, another England debutant, completes the starting XV at full-back, with Quins centre Joe Marchant and number eight Alex Dombrandt notable absentees from the squad.
Uncapped trio Jamie Blamire, Trevor Davison and Ben Curry – twin brother of England star Tom – are among the replacements.
Jones said: “Over the past three weeks our biggest message to the players is what an opportunity this is to show what they can do and make their mark with England.
“They’ve applied themselves as a group and worked very hard individually during this camp to reach their personal bests.
“Now it’s all about coming together as a team, gelling and putting in a good performance at the weekend.”
England: Steward; Cokanasiga, Slade, Lawrence, Malins; Smith, Randall; Genge, Langdon, Heyes, McNally, Ewels, Ludlow (capt), Underhill, Chick.
Replacements: Blamire, Obano, Davison, Hill, B Curry, Ludlam, Robson, Umaga.