Due largely to their League Cup, FA Cup and UEFA Champions League commitments, City have fallen off the pace at the top - with Brendan Rodgers' side taking full advantage to move four points ahead of the 2011-12 champions.
With just the Premier League left to focus on, manager Manuel Pellegrini can ill-afford any more slip-ups following last Saturday's 1-1 draw at Arsenal.
Pellegrini's men have made the Etihad a fortress this season, winning 13 of their 14 league games on home soil.
The solitary defeat came against Chelsea in February, but City's response has been to take 14 points from six league games since then.
Pellegrini could be without leading goalscorer Sergio Aguero this weekend, with the striker not having featured since limping out of their Champions League defeat to Barcelona in March.
However, Southampton boss Mauricio Pochettino insists that he would welcome the Argentina international's return.
"I would like to play against him," he said. "I always want to face the best."
Pochettino's charges - who earned a 1-1 draw at home to City, when Aguro was on target for the visitors - have found their goalscoring touch lately, hitting 10 in the last three games.
English trio Jay Rodriguez, Adam Lallana and Rickie Lambert have been Southampton's main source of inspiration, with all three having found the net in Saturday's 4-0 win over Newcastle as they moved back into eighth.
And defender Luke Shaw - who could join the likes of Lallana, Rodriguez and Lambert in England's World Cup squad - feels that the sky is the limit for Southampton.
"I think in the next year or so we can be challenging the top five teams," he said.
"They've got to get the manager down on a long-term contract, which will probably be the first thing they try and do."
Victor Wanyama could return for Southampton following a calf problem, although Kelvin Davis (back), Nathaniel Clyne (groin) and Maya Yoshida (knee) remain sidelined.
