Wing Ollie Hassell-Collins will make his England debut in Saturday's Six Nations opener against Scotland at Twickenham.
Manu Tuilagi is left out of the 23-man matchday squad and Joe Marchant starts at outside centre in Steve Borthwick's first game as head coach.
Captain Owen Farrell will start at 12 and partner fly-half Marcus Smith.
Flanker Ben Curry will earn a second England cap 17 months after his first, stepping in for injured brother Tom.
Borthwick said Twickenham fans - some of whom booed England when they lost to South Africa in November - would witness "the start of the next chapter of English rugby".
He said: "The players are determined to play with the commitment, fight and desire that is at the very heart of representing England, the sort of passion that our tremendous supporters rightly expect."
Jack van Poortvliet is England's starting scrum-half, pushing the more experienced Ben Youngs, who has 121 England caps, to the bench.
Wing Max Malins returns to the back three, where Freddie Steward starts at full-back.
In the front row, hooker Jamie George will start - he has completed his return to play after concussion - as Luke Cowan-Dickie is injured.
Ollie Chessum partners Maro Itoje in the second row and Curry is joined by Lewis Ludlam in the back row, with Alex Dombrandt at number eight.
On the bench, hooker Jack Walker may make his debut, veteran prop Dan Cole could earn his 96th cap and Anthony Watson may return to the back three following injury.
New era, new wing
Hassell-Collins - called up to England training squads under previous head coach Eddie Jones - has performed consistently for London Irish this season.
Borthwick suggested he was looking to the future on the wing when he left Jonny May and Jack Nowell out of his Six Nations squad last month.
Hassell-Collins, 24, offers speed, solidity under the high ball and in defence and is sure to be tested in an intense Calcutta Cup atmosphere.
Tuilagi, 31, has been an England regular since his debut in 2011 but has been hampered by injuries throughout his career.
He is overlooked despite being fit as Borthwick turns to Marchant with Henry Slade, Elliot Daly and Dan Kelly injured.
Tuilagi's power may be missed, but Marchant will bring pace and dynamism alongside Harlequins team-mate Smith.
Farrell was expected to start at fly-half before Slade's injury meant he had to step out to 12 and make way for Smith.
England seek a revival under Borthwick before the World Cup begins in September. They won five of 12 Tests in 2022 and only two of five matches in last year's Six Nations.
Scotland are the Calcutta Cup holders, having won 20-17 at Murrayfield last year, and claimed a first win at Twickenham since 1983 on their most recent visit in 2021.
England: Steward; Malins, Marchant, Farrell (capt), Hassell-Collins; Smith, Van Poortvliet; Genge, George, Sinckler, Itoje, Chessum, Ludlam, B Curry, Dombrandt.
Replacements: Walker, M Vunipola, Cole, Isiekwe, Earl, Youngs, Lawrence, Watson.
Scotland: Hogg; Steyn, Jones, Tuipulotu, Van der Merwe; Russell, White; Schoeman, Turner, Nel; R Gray, Gilchrist; Ritchie (capt), Crosbie, M Fagerson.
Replacements: Brown, Bhatti, Berghan, J Gray, Dempsey, Horne, Kinghorn, Harris.
Analysis - 'dynamism over power'
BBC rugby union correspondent Chris Jones
A new regime and a new approach.
For years England coaches have picked Tuilagi - when fit - come what may, but Borthwick has gone instead for the pace and athleticism of Marchant.
It points to a preference for dynamism and mobility over power, with the selection of Curry and Ludlam on the flanks supporting this.
Hassell-Collins has waited for his chance on the wing, with Borthwick hailing his form over a number of seasons for London Irish as he rewards a number of players for their Premiership performances.