The Portuguese playmaker has recovered from a leg injury sustained in the 3-1 win over Red Star Belgrade in City's opening Group H fixture two weeks ago, and Pep Guardiola has decided to throw him straight into the first XI.
Stones, meanwhile, has been named on the substitutes' bench after recovering from a muscle issue that has kept him sidelined since the Community Shield loss to Arsenal in August.
Guardiola has made a total of five changes to the side that lost 2-1 to Wolverhampton Wanderers in the Premier League last weekend, with Bernardo, Rodri, Rico Lewis, Jack Grealish and Josko Gvardiol - a summer signing from Leipzig - all returning to the first XI.
Gvardiol replaces Nathan Ake at left-back, joining Kyle Walker, Ruben Dias and Manuel Akanji in the back four, while Lewis and Rodri - who returns after missing two domestic games due to suspension - start in midfield at the expense of Mateo Kovacic and Matheus Nunes.
Julian Alvarez and Jeremy Doku have dropped down to the substitutes' bench, as Grealish, Bernardo and Phil Foden provide support in attack for Erling Haaland, who scored five goals in his last meeting against Leipzig in a 7-0 last-16 win earlier this year.
As for Leipzig, Marco Rose has made two changes to the lineup that started the 2-2 draw with Bayern Munich in the Bundesliga last weekend, with Lukas Klostermann replacing the injured Benjamin Henrichs at right-back and Nicolas Seiwald starting ahead of Kevin Kampl in centre-midfield.
Xavi Simons and Emil Forsberg will continue in advanced midfield roles in behind strikers Yussef Poulsen and Lois Openda, while Timo Werner is fit to make the bench following a spell out with a back problem; Benjamin Sesko is also among the replacements for the hosts.
RB Leipzig: Blaswich; Klostermann, Simakan, Lukeba, Raum; Simons, Seiwald, Schlager, Forsberg; Openda, Poulsen
Subs: Gulacsi, Lenz, Haidara, Werner, Baumgartner, Carvalho, Sesko, Kampl
Manchester City: Ederson; Walker, Akanji, Dias, Gvardiol; Lewis, Rodri; Bernardo, Foden, Grealish; Haaland
Subs: Ortega, Carson, Phillips, Stones, Ake, Kovacic, Doku, Alvarez, Gomez, Nunes, Bobb