Flanker Macleod replaces injured captain Jac Morgan to make his tournament debut and is joined by club teammate Eddie James after the duo both missed the Autumn international campaign.
Bristol-based Louis Rees-Zammit starts at full-back, having not played in the Six Nations since 2023 with Wales winless in the tournament in that period.
Rees-Zammit, 25, is joined in the back three with Josh Adams and in-form Scarlets wing Ellis Mee. Blair Murray and Tom Rogers both miss out.
Ospreys Dewi Lake captains the side at hooker. Joining Lake in the front row are Leicester Tigers Nicky Smith at loosehead prop and Bath’s Archie Griffin, who made his Wales debut against the same opposition in the 2024 Championship, at tighthead prop.
Exeter Chiefs Dafydd Jenkins and France-based Adam Beard pair up in the second row.
Macleod is selected at openside flanker, Cardiff’s Alex Mann at blindside, with Dragons Aaron Wainwright at number eight.
Gloucester’s Tomos Williams is named scrum-half, and is partnered at half back with Ospreys Dan Edwards at fly-half.
James, making his second start from Wales at outside centre, is joined in midfield by Cardiff’s Ben Thomas.
There are six forwards and two backs among the replacements. Tomas Francis is set to make his first appearance for Wales since the Rugby World Cup in 2023. Hooker Liam Belcher and prop Rhys Carre join Francis as front row cover for Wales.
Ospreys Harri Deaves, who won his first cap against New Zealand last November, Ben Carter, and Taine Plumtree are the other forward replacements.
Mason Grady is in line to make his first outing for Wales since the 2024 Autumn Nations Series, and Kieran Hardy provides cover at scrum half.
Wales have lost 21 out of their previous 23 internationals, with the only victories against Japan in Kobe and Cardiff in 2025.
The defeats include a record 18-Test losing run and record home losses against England, Argentina, and South Africa in the last calendar year.
Wales have not won a Six Nations match since March 2023 against Italy in Rome, with the record of 11 successive defeats resulting in two winless tournaments in which they have picked up consecutive Wooden Spoons for finishing bottom.
In contrast, England have won their past 11 games and are ranked third in the world.
Speaking on his selection, Wales head coach Steve Tandy said:
“Wales v England is always a special game with all the history behind the fixture. We know they’re playing some outstanding rugby and they’re in great form. But I know how much it means to our players playing for the nation and representing Wales.
“The way the squad trained this week has been great. I want to see us get out and really attack the game on Saturday and give the best account of ourselves. Opening the Six Nations at Twickenham is historic, and it’s something we can’t wait to do.”
[Lead image: Huw Evans Picture Agency]
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