The first ever competitive meeting between the two sides will be held at the neutral venue due to coronavirus restrictions, and Liverpool will be looking to take advantage of Leipzig's lack of a home fixture in the two-legged tie.
Plenty has changed for both of these teams since they were last in Champions League action in December, but Liverpool in particular will be hoping that the return of European football will bring about another change in fortune.
The six-time European champions have won just five of their 15 games across all competitions since their final group game, losing six times including each of their last three outings.
The most recent of those - a quickfire collapse against Leicester City on Saturday - saw the defending English champions fall 13 points off the pace set by Manchester City, having played a game more than the leaders.
Such was the damaging nature of the defeat that manager Jurgen Klopp publicly conceded that their title defence is now over, leaving the Champions League as their only remaining route to silverware this season.
However, the likelihood of being crowned kings of Europe for a seventh time appears to diminish with each passing game at the moment, with those three successive defeats to Brighton & Hove Albion, Manchester City and Leicester leaving Liverpool in a serious battle to secure their place in this competition again next season, yet alone win it this term.
With a Merseyside derby looming at the weekend there is no let-up for Liverpool at the moment, and should their poor form continue much longer then their situation could get significantly worse before it gets better again.
The defeat to Leicester was the clearest sign yet that Liverpool are no longer the self-styled 'mentality monsters' that have been one of Europe's most feared teams over the last three years, but their record in this competition will still leave relative novices Leipzig wary.
In terms of pedigree in this competition there could hardly be more between these two sides, and following their run to the semi-finals last season it is easy to forget that this is only Leipzig's third Champions League campaign, and second experience of the knockout rounds.
Leipzig swept Liverpool's domestic rivals Tottenham Hotspur aside at this stage last season, before going on to beat Liverpool's last-16 conquerors Atletico Madrid, and this term they also managed to qualify from a very difficult group.
A 3-2 triumph over Manchester United on matchday six secured their place in the last 16 as runners-up to Paris Saint-Germain, although they conceded 12 goals in the process - the worst record of any team left in the competition.
Since that win over Man United, Leipzig have lost just twice in 13 games across all competitions, keeping nine clean sheets in that time to suggest that those group-stage defensive issues have now been solved.
While their opponents on Tuesday come into this match off the back of three straight defeats, Leipzig go into it having won each of their last four games, most recently beating Augsburg 2-1 on Friday night.
That has lifted them up to second in the Bundesliga standings, four points adrift of perennial leaders Bayern Munich, although that gap could grow when Bayern face Arminia Bielefeld on Monday night.
A second-placed finish would still equal their highest ever league standing, though, while claiming the scalp of Liverpool would be one of the biggest victories in their short European history.
The Reds are unbeaten in their last 10 meetings with German clubs stretching back to 2002, though, while they have won 15 of their previous 17 two-legged ties against Bundesliga opposition.
RB Leipzig Champions League form: WLWLWW
RB Leipzig form (all competitions): WLWWWW
Liverpool Champions League form: WWWLWD
Liverpool form (all competitions): LWWLLL
Liverpool could be without as many as 10 first-team players for this match as their never-ending injury troubles continue to deepen.
James Milner was the latest to be struck down when he picked up a hamstring injury 17 minutes in to the weekend defeat to Leicester City, and he is expected to miss this game as a result.
Liverpool's options had further been depleted prior to their trip to the King Power Stadium, with new signing Ben Davies ruled out due to a knock and Divock Origi and Caoimhin Kelleher both absent too.
Davies and Origi have both since returned to training and so could be in contention for this match, while Naby Keita is also now training with his teammates again, although this match against his former club will come too soon after two months out.
Fabinho will be assessed after missing the Leicester match with a "small muscle issue", although his absence from training on Monday suggests that he will be unavailable once again.
Leipzig were able to welcome rumoured Liverpool target Ibrahima Konate back into their side on Friday night and he could be involved again alongside Dayot Upamecano, who was also linked with Liverpool but has now agreed terms to join Bayern Munich.
Justin Kluivert made the bench on Friday night too and so could play some part against the Reds, but this match is expected to come too soon for Emil Forsberg, Konrad Laimer, Benjamin Henrichs and Dominik Szoboszlai, the latter of whom is yet to make his debut for Leipzig since joining in January.
Tuesday will also see Peter Gulacsi face his former club, having spent five years at Liverpool without making a senior appearance.
RB Leipzig possible starting lineup:
Gulacsi; Mukiele, Upamecano, Klostermann; Adams, Sabitzer, Kampl, Olmo, Angelino; Poulsen, Nkunku
Liverpool possible starting lineup:
Alisson; Alexander-Arnold, Kabak, Henderson, Robertson; Thiago, Wijnaldum, Jones; Salah, Firmino, Mane
We say: RB Leipzig 2-1 Liverpool
None of Leipzig's previous 22 Champions League games has ended goalless, so this contest should at least promise goals.
The German outfit have been denied home advantage and the neutral venue should give Liverpool a slight advantage over the tie as a whole, but the form book firmly points at a Leipzig victory in this match.
Liverpool's front three will always fancy their chances of getting a crucial away goal, but we expect them to leave themselves with a deficit to overturn in the second leg at Anfield next month.