Jurgen Klopp's men go into the first leg of their last 16 tie on the back of a 3-0 humbling at Hamburg, but they face a side which has not played a competitive game since December.
Borussia Dortmund's bid to improve on last season's runner-up finish in the Champions League resumes at Zenit on Tuesday.
Jurgen Klopp's men progressed past Shakhtar Donetsk, Malaga and Real Madrid in the knockout stages to reach the 2012-13 final, before ultimately coming unstuck against fellow Bundesliga side Bayern Munich, losing 2-1 at Wembley as a result of Arjen Robben's 89th-minute winner.
Dortmund topped Group F this time around, albeit only narrowly after Arsenal and Napoli also finished on 12 points.
While the Italian side was eliminated from the Champions League, Zenit made it through to the last 16 with half as many points, having finished second in a group dominated by La Liga's Atletico Madrid.
Zenit's only win in Group G came against Porto, but that sole triumph combined with three draws proved enough to seal a place in the knockout rounds for the second time.
Dortmund, by contrast, had to win four matches to guarantee its progression – with a 2-1 victory at Marseille in matchday six ultimately proving crucial.
After enduring a shaky spell prior to the Bundesliga winter break, Dortmund looked set to return to Champions League action in fine form. However, the club was sensationally denied a fourth straight league win Saturday as relegation-threatened Hamburg recorded a shock 3-0 triumph at the weekend.
Klopp's side is now 20 points behind leaders Bayern following the champions' 4-0 win at Hannover on Sunday and a point adrift of second-placed Bayer Leverkusen.
Zenit, meanwhile, has not played a competitive match since its final Champions League group game on December 11 thanks to Russia's winter break, and the team does not return to domestic action until March 9.
Luciano Spalletti's team sits at the top of the Russian Premier League thanks to a superior head-to-head record against Lokomotiv Moscow, which also has 40 points, but has been inconsistent in recent friendlies.
CSKA Moscow, Trans and Metalurh Donetsk all suffered defeats to Zenit, but the Russians were beaten by Shakhtar Donetsk and Metalist Kharkiv.
Spalletti will have a full squad to choose from barring any late fitness problems, meaning Salomon Rondon – a January signing from Rubin Kazan – could make his Champions League debut.
For Dortmund, Marco Reus returned from injury against Hamburg and will be available once again. Mats Hummels (ankle) is a doubt and Ilkay Gundogan (compression of the spine), Sven Bender (pubic bone inflammation), Neven Subotic (knee) and Jakub Blaszczykowski (knee) are definitely out.