Pep Guardiola revealed prior to Wednesday's 5-0 win over Sparta Prague in the Champions League that Jack Grealish will be sidelined for between seven and 10 days with an unspecified injury, while Jeremy Doku will be out for "a little longer" with a muscle problem.
Both players are joined in the treatment room by Kevin De Bruyne and Kyle Walker, who are yet to make a full recovery from respective groin and knee injuries, while Rodri (ACL) and Oscar Bobb (leg fracture) remain long-term absentees.
With Man City's squad now down to its bare bones, Guardiola is unable to make wholesale changes for Saturday's contest, but he is expected to recall a few first-team stars, including goalkeeper Ederson at the expense of Stefan Ortega.
Left-sided defender Josko Gvardiol is expected to take the place of Nathan Ake, who started in midweek after missing the previous seven games with a muscle injury, while Ruben Dias could take the place of either John Stones or Manuel Akanji in central defence.
After making a cameo substitute appearance in midweek, Mateo Kovacic is expected to start in midfield against Southampton, while Guardiola may consider sticking with just the one pivot, allowing Phil Foden and Bernardo Silva to take up advanced central roles in behind striker Erling Haaland, who scored twice against Sparta Prague.
Savinho is the most likely candidate to start on the right wing, while Matheus Nunes could be rewarded for his impressive midweek performance - a goal and two assists - with another start in a makeshift role on the left flank.
Manchester City possible starting lineup: Ederson; Stones, Dias, Gvardiol; Lewis, Kovacic; Savinho, Bernardo, Foden, Nunes; Haaland