Pep Guardiola's side are bidding to win the competition for a fifth time in the last seven seasons and a third in a row, and they will be overwhelming favourites to make the last four at the expense of their lower-league opponents.
Oxford sit 49 places below the English champions in the football pyramid and go into the game without a win or a goal in their last three matches.
Here, Sports Mole looks at how Man City could line up for the contest.
Changes will be in the offing for Man City with one eye on the weekend's Premier League showdown with high-flying Leicester City, although Guardiola has often still fielded some of his star names in matches against lower-league opposition recently.
David Silva is unlikely to be risked unless 100%, having missed the last two games with a leg injury, while Sergio Aguero is almost certain to miss the match again as he pushes to be ready for Leicester's visit.
Kevin De Bruyne could be one of the players rested following his first-half masterclass against Arsenal on Sunday, meaning that Phil Foden is in line to start for a third consecutive match while Ilkay Gundogan may also feature.
One area where Man City are short is in defence, and the importance of protecting Fernandinho and Nicolas Otamendi with Aymeric Laporte and John Stones still sidelined could see Taylor Harwood-Bellis and Eric Garcia start at centre-back.