On 27 August 2021, Cristiano Ronaldo returned to the club from Juventus after 12 years away, having left for Real Madrid in 2009 for a world record transfer fee.

[6] The final pre-season game was at home to fellow Premier League side Everton on 7 August;[1] United were 3–0 up by half-time via goals from Mason Greenwood, Harry Maguire and Bruno Fernandes, before Diogo Dalot scored a fourth in the second half.

[9] The following week, United travelled to face Southampton, and went behind on the half-hour mark, when Fred deflected Ché Adams' shot past David de Gea for an own goal.

[10] That record was broken the following week, when on 29 August 2021, United travelled to face Wolverhampton Wanderers in the final match before the first international break of the season.

Raphaël Varane made his debut following his move from Real Madrid, and provided the assist as Greenwood scored the only goal of the game to secure a 1–0 win.

It took him until injury time at the end of the first half to open the scoring, turning home the rebound after Newcastle goalkeeper Freddie Woodman spilled a long-range shot from Greenwood.

[14] United then played host to Aston Villa on 25 September, and lost defenders Harry Maguire and Shaw to injury either side of half-time.

[15] United took the lead just before half-time in their first fixture in October, at home to Everton, when Anthony Martial scored his first club goal since the 9–0 win over Southampton in February; however, Andros Townsend equalised for the visitors 20 minutes into the second half.

Greenwood opened the scoring, but Youri Tielemans pulled Leicester level just after the half-hour, before Çağlar Söyüncü put them in front with 12 minutes to go in the match.

Marcus Rashford levelled the scores again in his first appearance since the UEFA Euro 2020 final, but Jamie Vardy restored Leicester's lead a minute later and Patson Daka added a fourth in injury time to end United's record-breaking away Premier League unbeaten streak at 29.

[18] With United on the verge of losing three league games in a row for the first time since December 2015, they travelled to play Tottenham Hotspur on 30 October.

Playing with five at the back following the return of Varane from injury and with Cavani starting up front alongside Ronaldo, United won the match 3–0.

Eric Bailly started in place of Varane, who had been injured in the Champions League match against Atalanta four days earlier, and it was the Ivorian defender who opened the scoring, albeit for the away side, as he put João Cancelo's cross into his own net.

As United searched for an equaliser, João Pedro and Emmanuel Dennis scored in added time to confirm Watford's victory.

Emile Smith Rowe opened the scoring for Arsenal in the 13th minute with a volley from just outside the penalty area while De Gea lay injured in the middle of the goal after Fred had trodden on his ankle.

[24] Carrick left the club immediately after the match, and Ralf Rangnick took over for the game against Crystal Palace on 5 December,[25] having been waiting to receive his work permit since his appointment on 29 November.

Ronaldo's header was disallowed for offside before João Moutinho scored the winner at the 82nd minute to earn Wolves their first win at Old Trafford since 9 February 1980, when Wolverhampton also won 1–0.

[37] Visiting Burnley on 8 February, United went ahead at 12th minute via Varane but the goal was ruled out after Maguire fouled Jay Rodriguez in the build-up.

Maguire and Fernandes put the visitors two ahead in the first half before Rodrigo and Raphinha – the latter following an assist from former United player Daniel James – equalised via goals at the 53rd and 54th minutes.

[51] The next match saw United suffer their worst ever defeat against Brighton & Hove Albion by a score of 4–0, which meant they failed to qualify for the UEFA Champions League for the first time in three years.

Moisés Caicedo, Marc Cucurella, Pascal Groß and Leandro Trossard scored one each without any reply as United broke the club record for fewest wins in a Premier League season.

[63][64] Manuel Lanzini scored the only goal of the game in the ninth minute, giving West Ham their first win at Old Trafford in all competitions since the last day of the 2006–07 FA Premier League season.

In the first match, United were away to Young Boys and took the lead in the 13th minute when Cristiano Ronaldo shot through the goalkeeper's legs after a cross from Bruno Fernandes.

[67] Wan-Bissaka was given a two-match suspension for his red card and missed the next game against Villarreal at Old Trafford, along with fellow defenders Shaw and Maguire.

[69] Three weeks later, United hosted Atalanta for the first time at Old Trafford, and the away side were 2–0 up within the first half-hour, as Mario Pašalić scored in the 15th minute before Merih Demiral doubled their lead in the 28th.

Ronaldo equalised in first-half injury time, assisted by a backheel from Fernandes, making him the first Manchester United player to score in four consecutive Champions League matches since Ruud van Nistelrooy in 2003.

Atalanta went back in front just over 10 minutes into the second half through Duván Zapata, only for Ronaldo to score another late goal to save a point for United.

Rangnick named just seven of a possible 11 substitutes and gave three academy graduates their first-team debuts: Tom Heaton, Zidane Iqbal and Charlie Savage.

Another academy graduate Mason Greenwood open the scoring inside nine minutes before Donny van de Beek made a mistake that allowed Fabian Rieder to equalise and end the match at 1–1.

João Félix opened the scoring for Atlético with a diving header past former Atlético goalkeeper David de Gea in the 7th minute, before Anthony Elanga scored the equaliser following a pass from Bruno Fernandes 10 minutes from time; this made Fernandes the first player in Champions League history to assist in six consecutive appearances for an English club, breaking the record held by David Beckham – also for United – since 1998, while Elanga became United's youngest ever goalscorer in the Champions League knockout stage at 19 years 302 days.