The influential Argentine striker has missed three weeks of action with a hamstring strain picked up in the Champions League last-16 first leg against Barcelona.
He admitted this week that he is wary of rushing back so as not to jeopardise his World Cup hopes, but reports on Thursday claimed that he was poised to be named in the 18 for the visit of the Saints.
In his absence, City's other forwards have scored only three times in eight games, although Yaya Toure's exploits in front of goal have kept them firmly in touch at the top of the table.
Their opponents at the Etihad Stadium this weekend have had to deal with another week of speculation linking their boss and biggest names with moves away from Southampton in the summer.
Mauricio Pochettino has reportedly become Tottenham Hotspur's number one managerial target, while Liverpool maintain an interest in Luke Shaw and are believed to have joined the race for Adam Lallana.
Frenchman Morgan Schneiderlin is also hopeful of making it to Brazil, but may have to be content with a place on the bench, with James Ward-Prowse retained in midfield alongside Steven Davis and Jack Cork.
With the recovering Aguero yet to reach full fitness, Edin Dzeko is likely to continue as City's lone striker, with support coming from a trio of attacking midfielders and Toure in an initial holding role.
Victory would take the visitors to within three points of English champions Manchester United, who are seventh in the table, but City have only lost once domestically at Eastlands all season.
Man City: DWWWLL
Possible starting lineups
Man City: Hart; Zabaleta, Demichelis, Kompany, Clichy; Toure, Fernandinho; Milner, Silva, Nasri; Dzeko
Southampton: Boruc; Chambers, Fonte, Lovren, Shaw; Davis, Cork, Ward-Prowse; Lallana, Rodriguez, Lambert
Sports Mole says: 3-1