The delayed season started for Rotherham on 5 September 2021, with a defeat on penalties in the EFL cup to League 2 side Salford City.

Chiedozie Ogbene required knee surgery, and was ruled out until at least January; Clark Robertson suffered a broken foot, which ruled him out until the end of the winter; Shaun MacDonald broke his leg in the game against Stoke City on 31 October, and was out until the new year; and Kieran Sadlier suffered an ankle injury in the game against Preston the following Saturday, keeping him side-lined for three months.

[4][5][6][7] In the run-up to Christmas, the club were hit by an outbreak of COVID-19, causing the postponements of the planned games against Derby County and Middlesbrough.

[8][9] They returned to competition on 29 December against Barnsley, under perceived threat of a points deduction if they did not complete the fixture, despite having an "obliterated" squad, and only being able to name six substitutes.

[10][11] The first scheduled game of 2021, at home against Cardiff City, was called off an hour before kick-off due to snow, adding to the fixture congestion the club would face later in the season.

[15] On 3 March 2021, the club beat Sheffield Wednesday 2–1 at Hillsborough Stadium, despite having Michael Smith sent off (a decision which was later overturned), claiming a first-ever league double over their South Yorkshire rivals.