With Juventus and Atletico Madrid widely expected to battle it out for spots one and two, these sides know that the fixtures against each other could prove pivotal to their chances of upsetting the odds.
Not since 2016-17 have Leverkusen graced the Champions League with their presence, so Wednesday will be a welcome return to the big time for a team that finished fourth in the Bundesliga last season.
It promises to be a difficult road ahead with Juventus and Atletico Madrid - both of whom have recently reached the final of the competition - coming up in Group D, but Leverkusen have a respectable record at this stage.
Indeed, the German outfit have reached the last 16 at least in seven of their last eight campaigns and made it all the way to the final themselves in 2002, when Zinedine Zidane's iconic volley helped them on their way to defeat at the hands of Real Madrid.
It was the other Madrid side that ended their participation in their most recent Champions League outing, so there will at least be an opportunity for revenge against Atletico this time around.
Peter Bosz's side will need to improve for that to happen, though; Bayer have only won one of their last six home Champions League matches and were knocked out of the Europa League at the round-of-32 stage last season.
Lokomotiv may take confidence from the fact that that defeat came at the hands of Krasnodar - a team they finished above in the Russian Premier League last season to pip them to the final automatic qualifying spot for the group stages.
It is the club's second successive campaign in the tournament proper, having not appeared since 2003-04 before that, although last season saw them lose five of their six group games in a section which included Porto, Schalke and Galatasaray - a relatively kind draw by Champions League standards.
Not since 2002 have Lokomotiv won a Champions League away game - including qualifiers - while they have lost each of their last four European outings on the road.
However, despite only sitting fifth in their domestic league table Lokomotiv are five points better off than the same stage of last season, while they are coming into this match off the back of a 1-0 victory over Sochi compared to Leverkusen's 4-0 hammering at the hands of Borussia Dortmund at the weekend.
Leverkusen form: WWWDL
Lokomotiv form: WWWDLW
Kai Havertz is arguably the jewel in Leverkusen's crown nowadays, and good performances on this stage will only fuel speculation that he could be set for a big-money move next summer, with Manchester United and Liverpool among the clubs reportedly interested,
Joel Pohjanpalo is their only absentee having been sidelined since March 2018 with a string of foot injuries, although he did finally return to training during the international break.
Solomon Kverkvelia and Aleksei Miranchuk are also out for this match, while manager Yuri Semin will be sweating over the fitness of Germany international defender Benedikt Howedes and Anton Miranchuk.
Leverkusen possible starting lineup:
Hradecky; Lars Bender, Tah, Sven Bender, Wendell; Aranguiz, Havertz, Demirbay; Bellarabi, Volland, Bailey
Lokomotiv possible starting lineup:
Guilherme; Zhivoglyadov, Howedes, Corluka, Ignatyev; Zhemaletdinov, Krychowiak, Joao Mario, Barinov, Rybus; Smolov
We say: Bayer Leverkusen 2-0 Lokomotiv Moscow
Lokomotiv are one of a clutch of teams good enough to reach this stage, but usually not good enough to put up much of a battle when they get here. That is not to say that they will make things easy for Leverkusen, but the hosts should still pick up all three points.