The 2021–22 season was Stoke City's 105th season in the Football League, the 45th in the second tier and eighth in the Championship.
Stoke had a busy summer transfer window with the permanent departure of 13 players, which enabled O'Neill to make several new additions to his squad. A new look squad began the season well, gaining 35 points from the first 23 matches and they were just outside the play-off places at the turn of the year. However a poor run of results from January saw Stoke drop down the league and finish in a mid-table position for a fourth consecutive season.
Pre-season
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. The club also posted a £87 million loss during the COVID-19 hit 2019–20 season with the losses blamed on the pandemic and "writing down" the value of the squad. 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. Coming into the squad were goalkeeper Jack Bonham, striker Sam Surridge, midfielder Mario Vrančić and defender Ben Wilmot.
The Stoke squad returned to Clayton Wood for pre-season on 28 June 2021. They played a behind closed doors game against Scottish side Hibernian which ended in a 1–1 draw. Michael O'Neill then took a selected group of players for a week long training camp in Belfast. Stoke ended their week in Belfast with a 6–0 win over Linfield. On their return to England, Stoke beat Crewe Alexandra 3–2 at Gresty Road. Stoke then beat Aston Villa 2–0, lost 2–1 at Wigan Athletic before ending their pre-season schedule with a 1–1 draw against Wolverhampton Wanderers.
Championship
August
Stoke began the season at home to Reading with supporters allowed back into stadiums for the first time since March 2020. Nick Powell scored the opening goal in the 25th minute but Reading equalised immediately through John Swift. Jacob Brown then nutmegged Rafael Cabral to restore Stoke's lead. 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. The first away match of the season saw Stoke and Birmingham City cancel each other out in a goalless draw. 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. Stoke continued their good start to the season with a 1–0 win against Nottingham Forest, Josh Tymon scoring his first goal for the club. City suffered their first defeat of the campaign on 28 August going down 3–0 at promotion favourites Fulham. On transfer deadline day Stoke brought in right-back Demeaco Duhaney on a short-term contract and forward Abdallah Sima on loan from Brighton.
September
After the international break Stoke faced Huddersfield Town. After the Terriers had taken the lead through Harry Toffolo just after half-time Stoke responded with Brown heading in a corner and an own goal from Matty Pearson which earned Stoke a 2–1 win and their best start to a season for 17 years. Stoke played Barnsley four days later and drew 1–1 with a Cauley Woodrow free-kick cancelling out Surridge's opener. The match ended in unsavoury fashion as after Tommy Smith had been sent-off for a foul on Claudio Gomes, tempers boiled over and a scuffle between coaching staff and players resulted in two Stoke staff and one Barnsley staff being dismissed. Stoke were then beaten 2–1 by Derby County who had announced their intention to enter administration the day before. Stoke bounced back with a 2–0 win against Hull City with Vrančić scoring his first goal for the club and Powell scoring a long range free-kick. Stoke missed several chances away at Preston North End with a Benjamin Whiteman free-kick cancelling out Powell's early header.