Stoke announced their retained list on 1 June 2021 with Jordan Cousins the only senior player leaving whilst James Chester and John Obi Mikel signed one-year contract extensions.

[3] Stoke were able to move on a number of players in the summer transfer window including, Benik Afobe, Moritz Bauer, Jordan Cousins, Peter Etebo, Lee Gregory, Mikel John Obi, Liam Lindsay, Bruno Martins Indi, Badou Ndiaye, Lasse Sørensen, Sam Vokes, Kevin Wimmer and Ryan Woods whilst Nathan Collins moved to Burnley for an estimated £12 million.

[4] Coming into the squad were goalkeeper Jack Bonham, striker Sam Surridge, midfielder Mario Vrančić and defender Ben Wilmot.

Liam Moore brought the Royals back level before new signing Sam Surridge scored on his debut to earn Stoke a 3–2 victory and their first opening day win since 2009.

[13] They then put in an impressive performance away at last seasons beaten play-off finalists Swansea City, winning 3–1 with goals from Powell, Clucas and Østigård whilst Joël Piroe scored a late consolation for the Swans.

[16] On transfer deadline day Stoke brought in right-back Demeaco Duhaney on a short-term contract and forward Abdallah Sima on loan from Brighton.

[33] Stoke dropped out of the play-off places at the end of November at the expense of Blackburn Rovers who beat them 1–0, Reda Khadra scoring the only goal.

[38] Stoke began a busy January with a second consecutive 2–1 home defeat this time against Preston North End where goals from Brad Potts and Andrew Hughes cancelled out a 35-yard strike from Ben Wilmot.

They made a great start with D'Margio Wright-Phillips scoring his first league goal in the opening minute but Rodrigo Muniz levelled straight from the restart.

[43] Stoke were very active the January transfer window with Danny Batth, Adam Davies and Sam Surridge leaving the club permanently whilst Alfie Doughty and Tom Ince left on loan.

Coming into the team were Lewis Baker, Taylor Harwood-Bellis, Phil Jagielka, Josh Maja, Liam Moore and Jaden Philogene.

Brice Samba was then sent-off after conceding a penalty which was converted by Baker but Ryan Yates scored in stoppage time to deny Stoke the win.

[50] The team then played away at the leagues bottom two clubs, Barnsley and Peterborough United and drew both matches and were also beaten by Cardiff City.

[58] On Good Friday Stoke played Bristol City in a match of poor quality a late cross-cum-shot from Jay Dasilva looped over Jack Bonham to earn the Robins the win.

[63] Stoke were drawn at home to EFL League Two side Leyton Orient in the third round of the FA Cup and won 2–0 with goals from Tom Ince and Tyrese Campbell.

[65] League One side Wigan Athletic were the opponents in the fourth round and Stoke again won 2–0 with goals from debutant Josh Maja and Jacob Brown.