But Pep Guardiola’s side can move ever closer to a fifth Premier League title with three points over Ralph Hasenhuttl’s Saints that would move them 14 points clear at the top of the Premier League table.
Southampton, meanwhile, did top the table in November but ten games without a win saw them slide down the table towards the relegation spots.
Ralph Hasenhuttl’s men managed to stop the rot with a 2-0 win at Sheffield United last weekend but the south coast club still lie seven points above the drop zone though do have a game in hand over their relegation rivals.
Here’s everything you need to know about Wednesday night’s Premier League clash.
The match will kick-off at 6pm GMT at the Etihad Stadium in Manchester.
The game will be broadcasted on Sky Sports Main Event and Sky Sports Premier League, with coverage starting at 5.30pm GMT.
Pep Guardiola confirmed he has a fully fit squad to choose from on Wednesday night but the Spaniard is expected to make several changes as they continue their run of seven matches in 20 days.
Kyle Walker, Phil Foden, Sergio Aguero, Aymeric Laporte and Ferran Torres were only some of the players left on the bench for the Manchester United defeat and they could all come into the side.
Southampton have been dealt a blow as star striker Danny Ings is now expected to miss three weeks of the season after coming off against Sheffield United.
Ibrahima Diallo and Kyle Walker-Peters have late fitness tests after niggles, while Theo Walcott, Oriol Romeu, Will Smallbone and Michael Obafemi are expected to be out for the long-term.
Manchester City: Ederson; Walker, Stones, Laporte, Zinchenko; Fernandinho, De Bruyne, Gundogan; Foden, Aguero, Torres
Southampton: Forster; Walker-Peters, Bednarek, Vestegaard, Bertrand; Armstrong, Diallo, Ward-Prowse, Minamino; Tella, Adams
The two teams went against the form book over the weekend but normality should resume here. Pep Guardiola’s side will be too strong even if the City boss makes several changes from the weekend derby loss. Man City 3-0 Southampton