The English side fell short in the European Cup last term but are seen by many as the favourites to lift the crown this season under the leadership of serial winner Pep Guardiola.
City and Lyon are the favourites to progress from a group which also includes Hoffenheim and Shakhtar Donetsk, and both will be looking to get off to strong starts in Manchester on Wednesday night.
It will actually be the first ever meeting between these two teams, but Lyon won on their last visit to England, with that triumph occurring against Everton in the Europa League last season.
Here, Sports Mole looks at how City could line up on home soil.
Out: Kevin De Bruyne (knee), Claudio Bravo (Achilles)
Doubtful: Sergio Aguero (ankle), Benjamin Mendy (knee)
Kevin De Bruyne has handed City a huge boost by returning to training ahead of schedule following a knee injury, but this match will come too soon for the Belgium international.
City are also expected to be without the services of Sergio Aguero, who had to be withdrawn during Saturday's 3-0 win over Fulham in the Premier League due to an ankle problem, which should see Gabriel Jesus start up top.
Benjamin Mendy missed the clash with Fulham due to a knee injury, and the Frenchman is unlikely to be risked for this match, which should see Fabian Delph continue at left-back.