City boss Guardiola has undergone back surgery and he will miss the next two games while he recovers from the emergency operation.
This means assistant Juanma Lillo will take over the club's first-team duties for this clash and the champions' next fixture against Fulham.
Pep's absence could have an impact on Man City and that will increase the hopes of newly-promoted Sheffield United.
The Blades have lost both of their games back in the Premier League so will be desperate to pull off a shock result against the treble winners this weekend.
Sheffield United vs Man City: How to follow
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This Premier League clash will take place on Sunday, August 27.
Kick-off at Bramall Lane is scheduled for 2pm.
The game will be broadcast live on Sky Sports Main Event and Sky Sports Premier League with coverage beginning at 1pm.
talkSPORT will also keep you up to date with all the action.
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Sheffield United vs Man City: Team news
Oliver McBurnie could make his return from injury this weekend and is likely to take the place of William Osula.
New signings Vinicius Souza, Gustavo Hamer, Auston Trusty and Tom Davies may all feature while Anis Ben Slimane is out with a knock.
Kevin De Bruyne remains out as he begins a long spell on the sidelines after sustaining a serious hamstring injury.
However, Man City will be boosted by the return of Bernardo Silva who has been missing with illness over the week or so.
John Stones remains out with new signing Josko Gvardiol expected to start at centre-back alongside Ruben Dias and Manuel Akanji.
Sheffield United vs Man City: What has been said?
Guardiola's absence was announced on Tuesday.
A club statement read: "Pep Guardiola has today undergone a routine operation on a back problem.
The Manchester City boss has been suffering with severe back pain for some time lately, and flew out to Barcelona for emergency surgery performed by Dr Mireia Illueca.
"The surgery was a success, and Pep will now recover and rehabilitate in Barcelona.
"In his absence, assistant manager Juanma Lillo will oversee coaching of the first team on the training field and will assume duties on the touchline until Pep's return.
"He is expected to return after the forthcoming international break.
"Everyone at Manchester City wishes Pep a speedy recovery, and look forward to seeing him back in Manchester soon."
Sheffield United vs Man City: Match facts
Phil Foden created seven chances in open play for Manchester City against Newcastle in their 1-0 win on MD2, the most by a City player in a Premier League game since Kevin De Bruyne vs Norwich in July 2020 (also seven). Five of those were created following a ball carry, the most by a player in a game since Nathan Redmond in May 2021 for Southampton vs West Ham (7) and most by a Man City player in a game since March 2015 (David Silva vs West Brom, 5).
Gustavo Hamer scored on his Premier League debut for Sheffield United in their 2-1 defeat to Nottingham Forest. The only player to score in his first two Premier League appearances for the Blades is Brian Deane in their first two games in the competition in August 1992.
Julián Álvarez netted his 10th Premier League goal for Manchester City in their 1-0 win over Newcastle, with his last three goals all being the winning goal in the game. City have won all nine games when Álvarez has scored, with only Chris Smalling scoring in more Premier League games and ending on the winning side each time in Premier League history (11).
Man City manager Pep Guardiola has won 199 of his 268 Premier League games (D34 L35) and could become the sixth manager to win 200 in the competition. Victory would also see him become the fastest manager in English top-flight history to 200 victories, breaking José Mourinho's record (326 games).
None of Sheffield United's last 26 Premier League matches have ended as a draw (W7 L19) since a 1-1 draw with Brighton in December 2020. The last team to have a longer run were Arsenal between February and October 2022 (27 games in a row).
Manchester City have won their opening two Premier League games this season but haven't opened their season with three consecutive wins since their first under Pep Guardiola in 2016-17. Indeed, the reigning champions have only started a Premier League season with three wins once in the previous 11 seasons, Liverpool doing so in 2020-21.
Sheffield United have lost their opening two league games this season, only starting a season with three league defeats on three previous occasions - 1966-67 (top-flight), 1995-96 (second tier) and 2020-21 (Premier League).
Manchester City have conceded just one goal in their 10 Premier League games against Sheffield United. Their clean sheet ratio of 90% against the Blades is the highest one team has against another in the competition (min. five meetings).
Man City have never lost a Premier League game against Sheffield United (W7 D3), with their last top-flight defeat against them coming in February 1992 (2-4 at Bramall Lane).
Sheffield United are winless in their last eight league games against Manchester City (D2 L6) since a 1-0 home win in January 2000 while in the second tier.