The German side are flying high under highly-rated new manager Julian Nagelsmann, while Lyon will be aiming to improve on exiting last year's tournament at the last-16 phase.
For those on the outside, one might suspect that the appointment of Nagelsmann in June would precede something of a necessary transitional phase whereby results take a backseat in favour of developing a particular playing style, but Leipzig appear to have skipped this period entirely.
Indeed, under the tutelage of Nagelsmann, this Leipzig team has raced to second in the Bundesliga with four victories and a draw with champions Bayern Munich alongside comfortably beating Benfica in Lisbon on matchday one, all whilst playing a remarkably disciplined, high-tempo type based on pressing through the centre and swift counter-attacking movements.
Ever since Leipzig rose up the German football pyramid, the art of counter-pressing and producing fast, direct play through the middle has been central to the club's philosophy, aligning somewhat perfectly with what Nagelsmann famously brought to Hoffenheim before translating the same practice into his work with the Leipzig players over the summer.
Playing with a 4-2-2-2 system, Leipzig focus most of their attacks down the middle of the pitch, creating overloads between the opposition lines in order to attain as many passing lanes as possible into the lethal attacking duo of Yussuf Poulsen and Timo Werner, who already has seven goals in all competitions this term.
In front of their own supporters and buoyed by an excellent run of form, Leipzig will be determined to hit Lyon with optimum intensity and lay down a serious marker to the rest of Europe.
They come up against a Lyon team moulded in a similar image to the current project at Leipzig, with the Ligue 1 side - albeit with a different formation - also opting for a playing style which essentially relies on counter-pressing and feeding the ball down the centre in an attempt to break lines as quickly as possible, isolating the superb duo of Moussa Dembele and Memphis Depay up against opposition centre-backs.
Unlike Leipzig, however, these ideals enshrined by new manager Sylvinho have only manifested themselves in quick, unreliable bursts since the Brazilian took over in the summer, with the team clearly suffering from something of a hangover after the departure of Bruno Genesio, who spent four years at the club before joining Beijing Sinobo Guoan in May.
Genesio was the club's longest-serving manager of the 21st century and oversaw the development of a generation of young, talented stars like Dembele, Nabil Fekir and Bertrand Traore, all whilst being stifled by a piecemeal transfer budget between 2015 and 2017 as the club moved into its new stadium.
Lyon's performances and results this season have been reflective of a team going through transition: since scoring nine unanswered goals in their opening pair of Ligue 1 games, Sylvinho's men have failed to win a single match, drawing four times and losing twice, sometimes performing well in defeat like they did against Paris Saint-Germain and at other times looking clueless, as seen in a 1-0 home defeat to Nantes.
That said, Les Gones can head into their first European away game of the season knowing that they did not lose once on the road in the group stages last season, during which they claimed a sensational 2-1 win over Manchester City, becoming one of very few teams to outplay Pep Guardiola's men in their own stadium, along with an entertaining 3-3 draw against Hoffenheim - who were, interestingly enough, being managed by Nagelsmann at the time.
Recent RB Leipzig form: WDWWL
Recent Lyon form: DDLDL
Team News© Reuters
Nagelsmann remains without new signing Luan Candido after the youngster picked up an injury over pre-season, while Patrik Schick, a loan signing from Roma, is also definitely out due to an ankle problem.
Midfielder Kevin Kampl, however, could be in line for a return in time for the meeting with Lyon at the Red Bull Arena having not featured since August due to another ankle injury.
One to watch for Leipzig is young American starlet Tyler Adams, who has made 10 Bundesliga appearances for the German side and received his first senior international cap earlier this year. It remains to be seen as to whether he can return from a groin problem picked up over the summer in time for this game.
RB Leipzig possible starting lineup:
Gulacsi; Mukiele, Upamecano, Orban, Halstenberg; Demme, Haidara; Sabitzer, Forsberg; Poulsen, Werner
Lyon possible starting lineup:
Lopes; Dubois, Marcelo, Denayer, Marcal; Reine-Adelaide, Mendes, Aouar; Traore, Memphis, Dembele
We say: RB Leipzig 3-1 Lyon
There is something truly tantalising about this Leipzig team, currently motoring in the right direction under a coach who knows how to get the best out of his players, and you suspect the speed of their play, urged on by the home support, will be too much for a Lyon team still finding its feet under their new manager.