The Belgian playmaker has missed the last two matches due to a knock in his leg, but he has since "trained good" over the last few days according to Pep Guardiola and has been thrown straight back into the first XI.
De Bruyne is one of seven changes made to the side that beat West Ham United 3-0 on Wednesday, with Ederson, Rico Lewis, Manuel Akanji, Aymeric Laporte, Ilkay Gundogan and Phil Foden also coming into the first XI.
Stefan Ortega was handed his Premier League debut in goal last time out, but first-choice shot-stopper Ederson returns between the sticks this afternoon, while Lewis, Akanji and Laporte all start in defence at the expense of Kyle Walker, John Stones and Ruben Dias; Nathan Ake, meanwhile, retains his place at left-back.
Midfield lynchpin Rodri is rested and named on the substitutes' bench, with Gundogan taking his place, while De Bruyne comes in for Bernardo Silva.
Julian Alvarez, Riyad Mahrez and Erling Braut Haaland all keep their places in attack, but Foden is handed his first City start since March at the expense of Jack Grealish.
As for Leeds, newly-appointed head coach Sam Allardyce has made four changes to the side that lost 4-1 to Bournemouth under Javi Gracia last weekend, with the most notable change seeing goalkeeper Illan Meslier replaced by Joel Robles, who is handed his first Premier League start for the Whites.
Attacker Crysensio Summerville and centre-backs Robin Koch and Liam Cooper, the latter of whom is injured, have also made way from the first XI, with Junior Firpo, Maximilian Wober and Adam Forshaw all handed recalls.
Wober and Luke Ayling are set to form a centre-back partnership in between full-backs Firpo and Rasmus Kristensen, with Forshaw joining Marc Roca and Weston McKennie in centre-midfield.
Manchester City starting lineup: Ederson, Lewis, Stones, Dias, Ake, De Bruyne, Rodri, Gundogan; Bernardo, Haaland, Grealish
Subs: Ortega, Walker, Dias, Phillips, Stones, Grealish, Rodri, Bernardo, Gomez
Leeds United starting lineup: Robles; Kristensen, Ayling, Wober, Firpo; McKennie, Roca, Forshaw; Harrison, Bamford, Gnonto
Subs: Meslier, Koch, Struijk, Rutter, Summerville, Gray, Aaronson, Greenwood, Rodrigo