A planned fixture against Birmingham City was called off following an outbreak of Covid-19 among the Oxford squad.

Source: [citation needed] Oxford United's fixtures were announced on 24 June 2021.

[56] Oxford were drawn at home to Bristol Rovers in the first round.

[80] The U's were drawn into Southern Group H alongside Cambridge United, Stevenage and Tottenham Hotspur U21s.

[81] On 7 July, the fixtures for the group stage round was revealed.