The Citizens will be looking to return to winning ways after being held to a 1-1 draw away against Nottingham Forest in the Premier League last weekend.
Guardiola has been forced to make two changes from the side that picked up a point at the City Ground, with Kevin De Bruyne and Aymeric Laporte both missing out due to illness.
Phil Foden is the final man to drop out of the first XI, while Nathan Ake, Manuel Akanji and Riyad Mahrez have all been recalled for the clash in Germany.
The inclusion of Ake and Akanji will likely see City revert to a back four, with the defensive duo lining up alongside Kyle Walker and Ruben Dias, while Bernardo Silva is set to operate in a central midfield role alongside Rodri and Ilkay Gundogan.
Mahrez will take his place on the right flank, joining Jack Grealish and Erling Braut Haaland in a three-man attack; the latter of whom has scored six goals in four previous appearances against Leipzig.
As for Leipzig, Marco Rose has made two changes to the side that beat Wolfsburg 3-0 in the Bundesliga last weekend, with midfielder Konrad Laimer and left-back Marcel Halstenberg coming in for Amadou Haidara and David Raum.
Top scorer Christopher Nkunku, who scored a hat-trick in a 6-3 defeat against City at the Etihad Stadium last season, has recently returned from a three-month layoff with a knee injury and has been named on the substitutes' bench for tonight's game.
RB Leipzig starting lineup: Blaswich; Klostermann, Orban, Gvardiol, Halstenberg; Schlager, Laimer; Szoboszlai, Forsberg, Werner; Silva
Subs: Nyland, Nickisch, Simakan, Haidara, Poulsen, Nkunku, Raum, Henrichs, Kampl
Manchester City starting lineup: Ederson, Walker, Akanji, Dias, Ake; Gundogan, Rodri, Bernardo; Mahrez, Haaland, Grealish
Subs: Ortega, Carson, Phillips, Alvarez, Gomez, Perrone, Foden, Charles, Palmer, Lewis, Robertson