Pep Guardiola rested Erling Haaland, Ruben Dias, Bernardo Silva and goalkeeper Gianluigi Donnarumma, but Bayer Leverkusen took full advantage, beating City 2‑0 at the Etihad.
Alex Grimaldo opened the scoring in the first half, and Patrik Schick added a second after the break.
It’s City’s first home Champions League loss since 2018 and their second straight defeat after falling 2‑1 to Newcastle on Saturday.
The Blues have now slipped seven points behind league leaders Arsenal, having lost four Premier‑League games this season.