Their Portuguese opponents succumbed to a home defeat against RB Leipzig on the same night, which leaves Bruno Lage's team at the bottom of Group G.
While Zenit are focused on improving on their fifth place in Russia's top flight, Sergei Semak is aware that the club also have an opportunity to progress through to the knockout stages of European football's premier competition.
The draw in Lyon - the favourites to win the group - would have been regarded as a bonus, leaving Zenit in a position to take advantage in front of their own supporters at the Gazprom Arena.
They head into Wednesday's game on the back of a disappointing 1-0 setback at Lokomotiv Moscow on Saturday, which brought to an end their five-match unbeaten streak in all competitions.
However, they have now conceded just six goals from eight matches, and if Artem Dzyuba can continue his recent form in the final third, Semak will feel that his side are well set to at least match their last-16 appearance from three years ago.
Benfica will also be happy with their defensive work since the beginning of the campaign, with seven clean sheets having been kept in all competitions.
However, the defeats to Porto and RB Leipzig have the potential to derail their hopes of success on both the domestic and European scene, placing extra importance on achieving a result in Russia.
While avoiding defeat in a group full of well-matched teams will be number one priority, Lage will feel that there is enough quality in his squad to achieve maximum points.
Nevertheless, netting just four goals in their last outings will be a worry, and it has now been eight matches since any Benfica player contributed in the first half from open play.
Zenit St Petersburg form: WWDWWL
Benfica form: WWLWDW
Semak may opt to keep changes to a minimum, although Aleksey Sutormin is pushing for a starting role against the Portuguese side.
While Adel Taarabt's red card at the weekend will only result in a domestic ban, the Moroccan playmaker may still have to make do with a place among Benfica's replacements on Wednesday.
Zenit St Petersburg possible starting lineup: Lunev; Karavaev, Ivanovic, Rakitskiy, Santos; Ozdoev, Barrios, Sutormin; Driussi; Azmoun, Dzyuba
Benfica possible starting lineup: Vlachodimos; Almeida, Dias, Ferro, Grimaldo; Pizzi, Fejsa, Samiris, Rafa; Fernandes, Seferovic
We say: Zenit St Petersburg 2-1 Benfica
Zenit will hope to pick up a large portion of their points in Russia, and we expect them to earn a hard-fought win on Wednesday night. While Benfica have the quality to secure a positive result, they may leave space at the back if they go in search of a much-needed victory.
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