Manuel Pellegrini's side head into the match on a run of four games without a win in all competitions, including defeats to Stoke City and Bayern Munich in the Champions League.
Pablo Zabaleta will be unavailable for the tie, having been shown a red card during Sunday's 1-1 draw with Chelsea, while Stevan Jovetic and Fernando are doubtful with hamstring and groin injuries respectively.
Meanwhile, the Owls have already faced Premier League opponents in this competition this season, knocking Burnley out in the last round.
Former City youth player Keiren Westwood could face his former club, with the goalkeeper keeping five clean sheets in eight outings in the league this season.
Man City: WWLDLD
Sheffield Wednesday: WLWDWW
Possible starting lineups
Man City: Caballero, Kolarov, Nastasic, Boyata, Clichy, Fernandinho, Milner, Nasri, Sinclair, Lampard, Dzeko
Sheffield Wednesday: Westwood, Palmer, Loovens, Lees, Mattock, Hope, Semedo, Maguire, Maghoma, May, Nuhiu
Sports Mole says: 2-0