The Sky Blues will be aiming for their fourth league win on the spin against the Saints, who have made a slow start to the season with no wins in their first outings.
Pep Guardiola's men followed up a narrow win away at Leicester City last week with a 6-3 thrashing of RB Leipzig in the Champions League on Wednesday evening, with Jack Grealish netting on his first appearance in the competition.
It was revealed ahead of the tie that John Stones and Aymeric Laporte were both out with muscle injuries, and that the pair wouldn't be involved against the Hampshire outfit.
Following the confirmation of team news prior to the 15:00 (UK) kick-off at the Etihad Stadium, it has been revealed that Rodri and Oleksandr Zinchenko have joined the defensive duo on the sidelines.
Rodri appeared to have suffered a minor knock towards the closing stages of City's mid-week win over Leipzig, whilst Zinchenko played the full 90 minutes against the German side.
Fernandinho has slotted into the middle of the park for Rodri, while Kyle Walker's return to the right side of defence means that João Cancelo, who starred against Leipzig, will operate as left-back against Ralph Hasenhüttl's side.
Speaking ahead of the clash, City boss Pep Guardiola said: "We have two central defenders injured (Stones and Laporte), Rodri injured, Zinchenko injured. We are not in a good condition at the back," in an interview with Sky Sports.
"After the Champions League, it's always so demanding. We never select a team that we don't believe cannot win. You always select a team that you believe can do a good game."
READ MORE: Phil Foden set for Man City position change
Here are the confirmed teams from Saturday's tie in the east side of Manchester-
Manchester City: Ederson; Kyle Walker, Rúben Dias, Nathan Aké, João Cancelo; Bernardo Silva, Fernandinho, İlkay Gündoğan; Gabriel Jesus, Raheem Sterling, Jack Grealish
Substitutes: Scott Carson, Luke Mbete-Tabu, Joshua Wilson-Esbrand, Roméo Lavia, Kevin De Bruyne, Phil Foden, Riyad Mahrez, Cole Palmer, Ferran Torres
Southampton: Alex McCarthy, Tino Livramento, Jack Stephens, Jan Bednarek, Kyle Walker-Peters; Oriol Romeu, James Ward-Prowse, Mohamed Elyounoussi, Che Adams, Nathan Redmond; Adam Armstrong
Substitutes: Fraser Forster, Romain Perraud, Yan Valery, Lyanco, Mohammed Salisu, Ibrahima Diallo, Moussa Djenepo, Nathan Tella, Armando Broja
You can follow us for live updates here: @City_Xtra