Hoffenheim, meanwhile, have won just one of their last nine league games.
Indeed, despite topping their Europa League group to qualify for the knockout stages of European competition for the first time in the club's history, it has not been a particularly pleasant domestic period for Hoffenheim.
Sebastian Hoeness's side endured a nightmare 4-1 defeat at league leaders Bayer Leverkusen on Sunday, with Florian Grillitsch and Stefan Posch both sent off in the second half after Leon Bailey's first-half brace had given the hosts a commanding lead heading into the break.
Christoph Baumgartner had continued his fine form of late by pegging one back five minutes after the interval, but Florian Wirtz quickly restored Leverkusen's two-goal cushion before Grillitsch and Posch's ill-discipline left Hoeness's side with no chance of mounting a comeback long before Lucas Alario's last-minute penalty.
Hoeness must find a way to cope without two of his regular starters against one of the stronger sides in the league, with just one win in 10 league matches a real possibility by the final whistle on Wednesday.
Spirits are high at Leipzig, meanwhile, with a creditable draw at Bayern and a routine 2-0 home win against Werder Bremen on Saturday sandwiched by qualifying for the knockout stages of the Champions League for a second successive campaign with an impressive 3-2 win against Manchester United.
Julian Nagelsmann's were typically controlled against Bremen, restricting the visitors to only two shots on target across the 90 minutes, with Marcel Sabitzer's penalty and Dani Olmo's strike giving them a comfortable lead heading into the break.
Having only won once on the road in the Bundesliga this season, Nagelsmann will likely be imploring his side to treat the trip to a depleted Hoffenheim side like a home game, with Leipzig boasting a perfect record from their six matches at Red Bull Arena this season.
With Liverpool awaiting them in February as their last-16 Champions League opponents, Leipzig must ensure they remain relentless domestically in order to avoid losing any ground on the likes of Leverkusen and Bayern at the top of the table and head into that two-legged affair with maximum confidence of progressing.
Hoffenheim Bundesliga form: LLDDWL
Hoffenheim form (all competitions): WDDWWL
RB Leipzig Bundesliga form: LWDWDW
RB Leipzig form (all competitions): LWWDWW
Benjamin Hubner, Pavel Kaderabek, Sargis Adamyan, Ermin Bicakcic, Kostas Stafylidis and Jacob Bruun Larsen are all unavailable through injury, meanwhile, leaving Hoeness with very few options to change his side.
Leipzig, meanwhile, remain without long-term absentees Lukas Klostermann, Konrad Laimer and Fabrice Hartmann, while Hwang Hee-chan and Benjamin Henrichs will not make the trip to Hoffenheim due to coronavirus and a knee issue respectively.
Nagelsmann likes to rotate his side, so having not started in the win against Bremen, we can expect the likes of Angelino, Emil Forsberg and Tyler Adams to come into the starting XI given the quick turnaround between fixtures.
Hoffenheim possible starting lineup:
Baumann; Rudy, Vogt, Nordtveit, Sessegnon; Samassekou, Baumgartner; Gacinovic, Bebou; Dabbur, Kramaric
RB Leipzig possible starting lineup:
Gulasci; Mukiele, Konate, Upamecano, Angelino; Adams, Sabitzer; Nkunku, Forsberg, Olmo; Poulsen
We say: Hoffenheim 1-3 RB Leipzig
Given Hoffenheim's raft of absentees, we can envisage Leipzig recording only their second away win of the season on Wednesday in order to keep the pressure on the two sides currently above them in the table.
Nagelsmann's ability to rotate yet maintain positive results is an impressive part of his management, which can really come to the fore in midweek games.