The season covers the period from 1 July 2021 to 30 June 2022.

On 1 August 2021, manager Russell Martin departed the club to take up the vacant managerial position at Swansea City, with the buyout clause in his contract activated.

[2] On 3 August 2021, the club announced captain Dean Lewington would take over as interim manager whilst a permanent replacement was sought.

[7] A successor was announced on 13 August 2021, with Liam Manning being revealed as the club's first ever Head Coach.

[4] Milton Keynes Dons announced they will play friendly matches against King's Lynn Town,[8] Chelmsford City,[9] Bristol City[10] and Tottenham Hotspur[11] as part of their pre-season preparations.