The Citizens have an underwhelming record in European competition, but much is expected of them this time around following their incredible domestic success last time out.
Transferring their domestic form onto the continent has to be the biggest priority for Pep Guardiola this season, having seen his side fall far too early in the Champions League during his first two years at the helm.
For all the Catalan coach's pedigree, including two European Cups at Barcelona, City's best performance in Europe remains their run to the semi-finals under Manuel Pellegrini in 2015-16.
City racked up an unprecedented 100 points in the Premier League last season, adding to their EFL Cup success, and will go down as one of the top flight's greatest-ever sides thanks to the numerous records they broke along the way.
Adding a fourth Prem crown to their collection in the last eight seasons would be nice, of course, but achieving success on the continent is the biggest step for Guardiola and his men to take, especially having been crushed 5-1 by Liverpool in the quarters last term.
That was a tough defeat to take for the English champions, with their domestic rivals winning 3-0 at Anfield and then 2-1 at the Etihad Stadium. Following a run of 13 games without defeat at home in Europe, it is now two successive losses for the Citizens.
Basel were the other side to win here in 2017-18, albeit after losing the last-16 first leg 4-0 on their own patch, so turning this ground back into a fortress is the first task for Guardiola.
City stormed through to the knockout stages for a fifth successive campaign last time out, thanks in large to their home form as they won all three group matches - including a 2-0 success over Shakhtar Donetsk, with whom they have also been paired this year in Group F.
Wednesday evening's clash is the start of a run that will see the Citizens play three times in three competitions in the space of six days, with away trips to Cardiff City and Oxford United to follow in the league and cup. After claiming 13 points from the first 15 on offer in the top flight, scoring 14 goals in the process, momentum does not seem to be too much of a problem at this stage.
Recent form (all competitions): WWDWW
Lyon have become regulars in the Champions League again in recent years, qualifying for the group stage in three of the last four campaigns. Unfortunately for them, however, they have failed to advance any further in each of their last two participations in the competition.
They last reached the last 16 in 2011-12 and they had to settle for a place in the Europa League in 2017-18, with their European adventure coming to an end at the hands of CSKA Moscow in the third knockout round.
The 2010 semi-finalists have competed at this stage of UEFA's showpiece competition on 14 previous occasions, however, which is the most of any French side, and they will fancy their chances of escaping a group that also contains Shakhtar and newbies Hoffenheim.
Bruno Gensio's men do not have a bad record away from home on the continent, either, and they have performed admirably against English sides in recent times.
The 2-1 Europa League win over Everton at Goodison Park last year, courtesy of goals from Nabil Fekir and Bertrand Traore, made it one loss in their last six meetings against teams from the Premier League, and was one of three wins in five away fixtures in Europe.
Domestically speaking, though, Lyon have failed to push on from their third-placed finish in 2017-18, granting them an automatic spot in the Champions League group stage, as they have collected seven points from the first 15 on offer.
A 2-2 draw at Caen on Saturday led to more questions being asked of Gensio, two weeks on from a surprise 1-0 home loss to Nice, and now Les Gones are left playing catch-up on the likes of Paris Saint-Germain and next opponents Marseille.
European football could be a welcome distraction, then, with a positive result at the Etihad Stadium on Wednesday potentially kickstarting Lyon's season.
Recent form (all competitions): WLWLD
Leroy Sane took advantage of his return to first-team action by netting an early opener against the Cottagers, but rotation is the order of the day for Guardiola, so Riyad Mahrez could be brought back in.
In terms of the visitors, they can call upon former Celtic striker Moussa Dembele after the Frenchman played the full 90 minutes on his debut against Caen at the weekend.
That match also brought up a first goal in Lyon colours for Ferland Mendy, who last netted for Le Havre in October 2016, and the left-back is expected to start on the opposite flank to a familiar face in Rafael Da Silva - a player still well respected by Manchester United supporters, three years after leaving the club.
Elsewhere, Nabil Fekir remains a Lyon player after a move to Liverpool collapsed at the eleventh hour during the summer window, while Jason Denayer spent time on City's books up until recently and ex-Chelsea forward Bertrand Traore also has experience of English football.
Manchester City possible starting lineup:
Ederson; Delph, Stones, Laporte, Walker; D.Silva, Fernandinho, Gundogan; Sterling, Jesus, Mahrez
Lyon possible starting lineup:
Lopes; Rafael, Marcelo, Denayer, Mendy; Tousart, Ndombele, Aouar; Traore, Fekir, Dembele
Head To Head
Wednesday night's encounter at the Etihad Stadium will mark the first time that these two sides have faced off in a competitive fixture.
City have a positive record at home to French clubs in Europe, having won two and drawn one, although that most recent win - 5-3 against Monaco in 2016-17 - was not enough to keep them in the competition as they were eventually eliminated on away goals in the thrilling last-16 tie.
Lyon's most recent visit to England was that aforementioned 2-1 win over Everton in October 2017, four days before Ronald Koeman was sacked as Toffees manager.
We say: Manchester City 2-1 Lyon
Manchester City had won seven of their last eight home matches in Europe prior to successive defeats at the hands of Basel and Liverpool. Guardiola will see Wednesday night as a chance to get his side back up and running in that regard, but Lyon are no pushovers and return to England with nothing to lose.