The Citizens have won their last three matches on the continent, following a defeat to Les Gones in their opening fixture, to take control of Group F.
Despite a draw being enough to secure a qualifying spot with a game to spare, Pep Guardiola will no doubt be targeting victory to nail down first place and set up - on paper - an easier route to the final.
Here, Sports Mole looks at the selection decisions Guardiola has to make ahead of the midweek trip to France.
With 10 more games to play between now and the end of the year, Guardiola may be tempted to rotate his side on the back of the resounding 4-0 win at West Ham United.
At the same time, though, defeat to Lyon could take City's Champions League campaign down to the wire - depending on the result between Shakhtar Donetsk and Hoffenheim - so mass changes will likely be avoided.
Nicolas Otamendi came in for his first league start in two months for the trip to the London Stadium at the weekend, meaning a rest for John Stones.
England international Stones is expected to return to the fold on Tuesday, but Guardiola must decide whether to leave out Laporte for one of Vincent Kompany or Otamendi.
Bernardo is also thought to be back in contention after picking up a knock during the international break, while Phil Foden is in line for a recall to the starting lineup after performing well from the bench against West Ham.
Further forward, Gabriel Jesus netted a hat-trick against Hoffenheim on matchday four and may get the nod over Sergio Aguero for this one, and Riyad Mahrez is also raring to go after being benched in East London.