Barkley replaces Pelly Ruddock Mpanzu in midfield, while Reece Burke comes into central defence for Mads Andersen at Stamford Bridge.
The Hatters keep the same shape with Carlton Morris – who scored at the Amex Stadium – partnering Elijah Adebayo in attack.
Tim Krul takes his place on the bench following his arrival at Kenilworth Road from Norwich, and also among the substitutes is 17-year-old academy graduate Joe Johnson.
Hosts Chelsea meanwhile give a debut to new £115m signing Moises Caicedo in midfield.
Town: Kaminski; Kaboré, Giles, Burke, Lockyer, Bell; Nakamba, Chong, Barkley; Morris, Adebayo.
Subs: Krul, Andersen, Obgene, Berry, Woodrow, Mpanzu, Brown, Doughty, Johnson.
Chelsea: Sanchez, Disasi, Silva, Sterling, Fernández, Jackson, Chilwell, Gallagher, Caicedo, Colwill, Gusto.
Subs: Bergström, Beach, Cucurella, Madueke, Ugochukwu, Maatsen, Burstow, Moreira, Humphreys.
Referee: Robert Jones.
VAR: Paul Tierney.