City have won the Carabao Cup eight times, including six wins in the last nine seasons, while their opponents were finalists last season but lost out on penalties to Liverpool.
A number of players will be unavailable for Pep Guardiola's side, including the suspended Joao Cancelo (28) and long-term absentee Kyle Walker (32).
Some doubts also remain over the fitness of Erling Haaland (22), with Guardiola admitting that the Norwegian still hasn't fully recovered from injury.
There is a return to the squad for Kalvin Phillips (26), though, as he continues his recovery from shoulder surgery.
Chelsea are also hampered by a number of serious injuries, with the likes of Jorginho (30), Reece James (22), Ben Chilwell (25) and Kepa Arrizabalaga (28) all unavailable.
Both James and Chilwell received the devastating news that they will miss the World Cup with England, while Jorginho is a minor doubt for the game after picking up a foot injury.
Kepa will be out until after the World Cup, but the Blues have a capable deputy in the form of Edouard Mendy (30).
Players to watch: Julian Alvarez (22) has been mainly limited to appearances from the bench in the Premier League, but a first Carabao Cup start for the Argentinian could see him build on the six goals he has already scored. Raheem Sterling (27) has had a slow start to his Chelsea career, but could come back to haunt his former club on Wednesday evening.
Hot Stat: Manchester City have lost just four times in the Carabao Cup in the last eight years, even winning the competition four times in a row between 2017 and 2021.