The club kicked off the season by losing the Community Shield to Leicester City and was later knocked out of the EFL Cup by West Ham United in the fourth round, ending their unbeaten streak in the competition that had stretched to nearly five years.

In Europe, City were coming off their most successful Champions League campaign in history and looked to improve on last season's final loss to Chelsea.

City secured the league title by a single point on the final matchday with a dramatic 3–2 comeback victory overAston Villa.

City were unable to immediately recruit a like-for-like replacement for Agüero, and this season was notable for Guardiola's extensive use of a false 9 role.

[1] Supplier: Puma / Sponsor: Etihad Airways Euro 2020 began with 15 Manchester City first team players selected in the qualified squads, which was the joint-most representatives from a single club (shared with Chelsea).

Most of the pre-season transfer speculation concerned the potential replacements for Sergio Agüero, who had left at the end of the 2020–21 season after 10 years and as the club's all-time leading goalscorer.

Of the potential targets, Harry Kane was seen as the leading candidate, but was expected to command a significant and possibly record-breaking transfer fee from Tottenham.

[8] There was also speculation that Jack Grealish would be signed from Aston Villa on a similarly record fee to strengthen City's creative midfield and provide additional cover for Kevin De Bruyne, who had experienced several extended periods of injury absence during the previous seasons.

On 8 September, it was announced that Brazil and three other South American nations had invoked a five-day FIFA ban on Premier League players who had been called up for international duty for the 2022 World Cup qualifiers during the September international window, but who had been refused permission to travel by their clubs to avoid a 10-day quarantine period required by UK Government public health regulations when they returned from so-called "Red list" countries with high levels of COVID-19 infection.

[25] On 12 October, five City players started for England versus Hungary in their 2022 FIFA World Cup qualifier 1–1 draw at Wembley Stadium.

However, City had by then played all of the previous season's other top 5 clubs away from home, remaining undefeated and only dropping points in their 2–2 draw against Liverpool at Anfield.

[34] On 28 December, City announced that Spanish forward Ferran Torres would join Barcelona in the New Year for a reported fee of €55m (£46.3m) upfront and up to €10m (£9.3m) in possible add-ons.

Torres had not played for City since the League Cup victory against Wycombe in late September due to an injury picked up during the October internationals.

[37] On winter transfer deadline day, City announced that they had signed 22 year-old Argentine versatile forward Julián Álvarez for a reported £14.1 million fee from River Plate.

At the time, Álvarez was the current South American Footballer of the Year and the golden boot holder for the Argentine Primera Division.

[41] An outstanding team performance against their closest rivals saw City convincingly beat Manchester United 4–1 at home on 6 March with a brace apiece from Riyad Mahrez and man of the match Kevin De Bruyne.

[42] City drew 0–0 with Sporting on 9 March in the second leg of their Champions League round of 16 tie to win 5–0 on aggregate and qualify for the quarter-finals for the fifth season in succession.

[44] On a brighter note, the Blues qualified for their fourth consecutive FA Cup semi-final when they beat Southampton 4–1 at St. Mary's on 20 March.

[45] City returned from the March international break knowing they had up to 16 games of the season remaining over eight weeks, in which they could secure a treble of titles.

However, first City had to retake the top spot from Liverpool, which they successfully accomplished by beating Burnley 2–0 at Turf Moor on 2 April, after their rivals had defeated Watford by the same score at home earlier that day.

On 10 April, an exciting and high quality 2–2 home draw against Liverpool ensured City retained a single point advantage at the top of the league with seven games remaining.

The Blues managed to improve in the second half, with goals from Jack Grealish and Bernardo Silva nearly erasing the deficit, but Liverpool withstood the pressure to a nervous 3–2 victory, ending Citizens' hopes of the treble.

[47] Another three days later, on 26 April, Manchester City defeated Real Madrid 4–3 in an outstanding game at a capacity Etihad Stadium to take a slight advantage to the Santiago Bernabéu.

City scored in under two minutes, as Kevin De Bruyne finished the fastest goal in European Cup semi-finals history, and had held a two-goal advantage on three occasions during the match, while also squandering multiple good opportunities to increase the lead, only to see a resilient Madrid side reduce the deficit to a single goal, courtesy of a brace (which included a Panenka penalty) from Real Madrid's top scorer, captain and talisman Karim Benzema.

[52] City were able to put their shock and disappointment from the Bernabéu to one side and capitalise on this, opening up a three-point lead and a four-goal difference advantage after a 5–0 thrashing of revitalised Newcastle United with a brace from Raheem Sterling and another man of the match performance from Kevin De Bruyne.

[53] On 10 May, the club officially announced it had reached agreement with Borussia Dortmund to sign young Norwegian striker Erling Haaland on 1 July 2022 subject to completing terms.

[54] Another big 5–1 win away at Wolves on 11 May, including four goals from Kevin De Bruyne, and a 24-minute hat-trick (the third fastest from the start of a game in Premier League history), reduced City's target to getting a maximum of four points from two remaining fixtures to retain their title.

On 15 May, City fought back from conceding two first-half goals to draw 2–2 at West Ham, and could have won the match but for a late penalty miss from Riyad Mahrez.

[145] The quarter-final draw was held on 3 March 2022 prior to the tie between Everton and Boreham Wood on ITV by England manager Gareth Southgate.

The draw was subsequently redone three hours later and City were drawn against Sporting CP,[156] who they had last met and lost on away goals to in the last 16 of the 2011–12 UEFA Europa League.