Rookie centres Ollie Lawrence and Cameron Redpath will start for England and Scotland respectively in Saturday's Calcutta Cup clash at Twickenham.
Lawrence, 21, made his debut as England sealed a 2020 Six Nations title against Italy and has earned two caps since.
His inclusion means captain Owen Farrell starts at 10, with George Ford on the bench.
Redpath, also 21, played for England at youth level but chose to join Scotland for the 2021 Six Nations.
Lawrence and Redpath go head to head, having played in the same midfield for England Under-20s in 2019.
Bath centre Redpath - whose father Bryan is a former Scotland captain - lines up outside Finn Russell, who missed the Autumn Nations Cup with a shoulder injury.
England's Farrell returns to fly-half
The last time England head coach Eddie Jones dropped Ford to the bench was England's 2019 World Cup quarter-final win against Australia.
Farrell now steps in at 10, forming part of a physical midfield with Henry Slade outside Lawrence at 13.
With Manu Tuilagi ruled out because of an Achilles injury, Jones cited Lawrence's "power" as one of the reasons for his inclusion in the England squad back in October.
In an England pack missing five key forwards, there are starts for lock Jonny Hill and returning flanker Mark Wilson.
Bath prop Beno Obano is set for his debut off the bench, while experienced forward Courtney Lawes has also been named as a replacement after making his comeback from injury.
In the absence of the suspended Kyle Sinckler, Will Stuart will make his first Six Nations start at tight-head prop.
Prop Mako Vunipola, lock Joe Launchbury and flanker Sam Underhill are out injured, while prop Joe Marler withdrew from the squad for personal reasons.
"It was difficult to pick the 23 players. We've had a really good week of training. It's been very competitive but I've gone with what I feel is the strongest 23 for this week," said head coach Eddie Jones.
Turner steps up amid Scotland injuries
Scotland have also been hit by injury in their front row and George Turner starts at hooker in the absence of Fraser Brown and Stuart McInally.
Chris Harris continues at outside centre alongside newcomer Redpath as the side seek a first win at Twickenham since 1983.
"We have been really impressed with Cam's contributions in the time he has been with us in camp," said Scotland head coach Gregor Townsend.
Number eight Matt Fagerson features in a familiar forward pack, while in-form Newcastle back-row Gary Graham is poised to win his third cap from the bench.
There is also a return to the matchday squad for lock Richie Gray and Edinburgh hooker Dave Cherry could make his debut from the bench.
This game marks the 150-year anniversary of the sport's oldest fixture, with the first rugby international played between the two sides in Edinburgh in 1871.
Each starting Scotland player will have the corresponding name from the 1871 team embroidered onto their shirt, while England head coach Jones said the anniversary made the game "even more special".
Line-ups
England: Daly; Watson, Slade, Lawrence, May; Farrell (capt), Youngs; Genge, George, Stuart, Itoje, Hill, Wilson, Curry, B Vunipola.
Replacements: Cowan-Dickie, Obano, Williams, Lawes, Earl, Robson, Ford, Malins.
Scotland: Hogg (capt); Maitland, Harris, Redpath, Van der Merwe, Russell, Price; Sutherland, Turner, Z Fagerson, Cummings, J Gray, Ritchie, Watson, M Fagerson.
Replacements: Cherry, Kebble, WP Nel, R Gray, Graham, Steele, Van der Walt, Jones