The City boss also brings in goalkeeper Stefan Ortega Moreno and captain Kyle Walker for the fifth round clash at Kenilworth Road.
Ederson, Ruben Dias, Rodrigo and Phil Foden all move to the bench from the side that beat Bournemouth on Saturday.
Grealish makes his first return since being forced off in the Champions League win away to FC Copenhagen on February 13 while De Bruyne has been a substitute for our last two games.
The only first-team player not in the squad is Josko Gvardiol with the defender still not ready for action after his recent setback.
TEAMS
LUTON XI: Krul, Ogbene, Burke, Mengi, Bell, Doughty, Barkley, Clark, Chong, Woodrow, Morris (C)
Subs: Shea, Osho, Berry, Mpanzu, Hashioka, Townsend, Johnson, Nelson, Piesold
CITY XI: Ortega Moreno, Walker (C), Stones, Akanji, Ake, Kovacic, Nunes, De Bruyne, Bernardo, Grealish, Haaland
Subs: Ederson, Dias, Doku, Rodrigo, Alvarez, Gomez, Foden, Bobb, Lewis
Tactics
At his pre-match news conference, Guardiola said he was expecting a similar game to recent 1-0 wins over Brentford and Bournemouth.
So it wouldn’t be a surprise if we go with a similar set-up for what promises to be a tricky tie.
That would see Walker and Nathan Ake as full-backs either side of Manuel Akanji with John Stones pushing into midfield alongside probable holder Mateo Kovacic.
Bernardo Silva and De Bruyne could take positions just ahead of them if Matheus Nunes reprises his right-sided role with Grealish the other side of spearhead Erling Haaland.
WELCOME BACK, JACK
The City winger looked dejected when he was forced off in Denmark but thankfully the setback was not major.
Guardiola spoke about how important Grealish will be, between now and the end of the season.
Our boss said he had “a special quality” with his ability to draw defenders giving space elsewhere on the pitch while he can punish sides if they allow him to be free.
He scored the winner at Kenilworth Road when we met in the Premier League and another strike would be more than welcome on his return.
Keep calm and carry on
Ortega Moreno is recalled to the side for the FA Cup, a competition where he has an extraordinary record.
Since joining in the summer of 2022, he has started each of our nine ties and been on the winning side in every one before tonight.
He has not conceded a goal from open play and the only time he was beaten from the penalty spot in the win over Manchester United at Wembley in the final following the controversial handball decision against Jack Grealish.
The only moment Ortega Moreno has missed was the second half of the FA Cup victory over Bristol City at the same stage last season when he was replaced by Ederson as a precaution.
Stats, facts and milestones
This is the first FA Cup meeting between the two sides since January 1969, when City won a third round tie 1-0 at Maine Road.
City are unbeaten in our last nine meetings with Luton in all competitions, winning five, with our 2-1 win at Kenilworth Road in the Premier League this season our only previous meeting with the Hatters this century.
Luton are looking to reach the FA Cup quarter-final for the first time since 1993/94. They’ve gone out at the fifth round twice since then – against Millwall in 2012/13 and against Chelsea in 2021/22.
City have reached the FA Cup quarter-final in all but one of our seven previous campaigns under Pep Guardiola. The only failure was in 2017/18, when we lost 1-0 to Wigan Athletic in the fifth round.
This is the first time Luton have an FA Cup tie against the holders of the competition since 1986/87, when they eliminated Liverpool after two replays in the third round.
City have won each of our last eight FA Cup matches by an aggregate score of 25-1. We’ve won 32 of our 38 games under Guardiola in the competition (drawing one), with four of our five defeats coming in the semi-final.
