After playing out a 1-1 draw in the first leg in Germany three weeks ago, the Citizens require a victory on home soil to progress to the quarter-finals of Europe's premier club competition for the sixth successive year.
De Bruyne missed the first leg through illness and was benched for the 1-0 Premier League win over Crystal Palace last weekend, but the Belgian playmaker returns to the first XI to face Leipzig tonight.
Phil Foden is the unfortunate one to drop down to the substitutes' bench, with the inclusion of De Bruyne the only change Pep Guardiola has made to his starting lineup.
Protecting Ederson between the sticks, John Stones, Manuel Akanji, Ruben Dias and Nathan Ake will all continue in the back four, with Kyle Walker, Aymeric Laporte and Rico Lewis all named on the bench.
De Bruyne will be joined in a three-man midfield by Rodri and captain Ilkay Gundogan, while Erling Braut Haaland - who has scored 17 goals in 11 home games in the Champions League - will be supported in attack by Bernardo Silva and Jack Grealish.
As for Leipzig, Marco Rose has also made just one change to his starting lineup following last weekend's 3-0 win over Borussia Monchengladbach in the Bundesliga, with Kevin Kampl replacing Andre Silva.
Top scorer Christopher Nkunku - who scored a hat-trick in a 6-3 defeat at the Etihad last season - is ruled out through injury along with Xaver Schlager, while reported Man City target Josko Gvardiol - who scored the equaliser in the first leg - will partner Willi Orban at centre-back.
Manchester City starting lineup: Ederson, Stones, Akanji, Dias, Ake; De Bruyne, Rodri, Gundogan; Bernardo, Haaland, Grealish
Subs: Ortega, Carson, Walker, Phillips, Laporte, Alvarez, Gomez, Mahrez, Perrone, Foden, Palmer, Lewis
RB Leipzig starting lineup: Blaswich; Henrichs, Orban, Gvardiol, Raum; Haidara, Laimer, Kampel; Szoboszlai, Forsberg; Werner
Subs: Nyland, Nickisch, Simakan, Olmo, Poulsen, Klostermann, Silva, Halstenberg, Ba
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