Jurgen Klopp's men need three points to secure qualification for the next round in the south of France against the struggling Ligue 1 outfit.
Borussia Dortmund must win at Olympique de Marseille to be sure of reaching the last 16 of the Champions League.
Jurgen Klopp's men - runners-up to Bayern Munich last season - currently sit second in Group F courtesy of their superior head-to-head record against Napoli.
Yet any slip-up at the Stade Velodrome would give the Italian side, which hosts Arsenal on matchday six, an opportunity to qualify.
Victory will guarantee Dortmund's progression as it also has the edge over Arsenal, which currently holds a three-point cushion at the top of the group, when it comes to meetings between the two.
Striker Robert Lewandowski is confident his side have what it takes to perform under pressure in France, telling his club's official website: "I am sure that we will get there (to the last 16)."
However, Lewandowski and his teammates suffered a blow this weekend when a 1-0 home defeat to Bayer Leverkusen saw Dortmund slip 10 points behind Bundesliga leaders Bayern Munich.
Sven Bender and Nuri Sahin each suffered ankle injuries in that match and the former will definitely miss out against Marseille, with Sahin rated as extremely doubtful.
While Dortmund's preparation for Wednesday's fixture can hardly be considered ideal, Marseille has suffered even greater disruption.
Coach Elie Baup was sacked Saturday, 24 hours after a 1-0 defeat to Nantes that saw the south coast club lose more ground on the top three in Ligue 1.
Sporting director Jose Anigo has been placed in temporary charge of Marseille and will aim to help prevent the team from finishing the Champions League group stage without a point to their name.
Marseille was beaten 3-0 at Dortmund in October's reverse fixture, with Lewandowski scoring twice either side of a goal from Marco Reus.
Fifteen teams have previously ended the group stage pointless, although Marseille can perhaps take inspiration from a 3-0 home victory over Dortmund in the 2011-12 Champions League.