Nathan Ake returned to training last week and is in line to feature in the squad for the first time since Boxing Day.
City have no other injury or suspension concerns, meaning that Guardiola can rotate his squad on the back of Sunday's 2-0 loss to Manchester United.
Sergio Aguero was once again an unused substitute against Man United, but the striker is in need of minutes and this could be a good opportunity to get him back in form.
Raheem Sterling has been involved in 11 goals in 16 Premier League games against Southampton - seven goals and four assists - but he is expected to be given a breather on Wednesday.
Man City possible starting lineup: Ederson; Walker, Dias, Laporte, Zinchenko; Silva, Fernandinho, Gundogan; Torres, Aguero, Foden
Watch the Sports Mole Football Shorts prediction for this game below: