Now under the stewardship of former Arsenal and Barcelona man Sylvinho, Lyon reached the last 16 of the competition in 2018-19, while Zenit are gracing this stage for the first time since 2015-16.
Lyon won plenty of admirers during the group stages of last season's competition - not least when they sent shockwaves around Europe with a 2-1 triumph away to Manchester City on matchday one.
The shock result against a side many tipped as favourites to lift the trophy proved to be comfortably the high point of their campaign, though, and they are winless in six Champions League outings since.
The Ligue 1 outfit drew their next five group games - including an admirable 2-2 result at home to Man City - before also holding Barcelona in the first leg of their last-16 clash, although they were swept aside at Camp Nou to end their run.
A summer of change has followed at the Groupama Stadium, with key players such as captain Nabil Fekir, Ferland Mendy and Tanguy Ndombele among 13 to leave the club during the transfer window - not to mention the departure of head coach Bruno Genesio.
There will be plenty of intrigue surrounding how they perform this time around, then, and they will have been pleased to avoid any of the genuine European heavyweights in the draw.
For Zenit it is a relatively kind return to Champions League action following a three-year absence, with Benfica and RB Leipzig being drawn alongside them in Group G.
The Russian outfit were seeded in pot one for this season's competition, but the three other teams in the group have all had more recent Champions League experience, and Benfica actually knocked them out of the tournament on their most recent taste of it.
Zenit have had to settle for Europa League football since then, reaching the round of 16 last season having begun in the third qualifying round - where they recovered from a 4-0 defeat in the first leg to record a remarkable 8-1 win after extra time against Dinamo Minsk.
The odds of similar drama in their opening European outing of this season are slim, and the visitors may even be content with a draw having failed to win any of their last nine continental games away from home - a run which includes seven defeats and stretches back to 2017.
Lyon, meanwhile, have lost just one of their last 14 European home games, although the French outfit are winless in their last three domestic matches whereas Zenit have begun the defence of their title by quickly rising back up to the top of the table.
Lyon form: WWLDD
Zenit form: DWDLWW
Depay and Dembele in particular have begun the season in fine form, scoring nine goals between them in just five games.
Aouar, meanwhile, returned from a groin injury during Friday night's 2-2 draw with Amiens and should be fit to feature again in this match.
Zenit, meanwhile, will be without former Barcelona winger Malcom, who was an unused sub in both legs against Lyon in the round of 16 last term and is now sidelined with a hip injury until early October.
Lyon possible starting lineup:
Lopes; Tete, Denayer, Andersen, Dubois; Mendes, Tousart, Aouar; Traore, Dembele, Depay
Zenit possible starting lineup:
Lunev; Smolnikov, Ivanovic, Rakitskiy, Santos; Kuzyaev, Barrios, Ozdoev, Zhirkov; Azmoun, Dzyuba
We say: Lyon 2-0 Zenit
In what could turn out to be a very tight group it may be the home records which make the difference. Lyon drew all of their home group games 2-2 last season, but we are backing them to have enough to pick up all three points this time around, particularly considering Zenit's away woes in Europe.