Andre Villas-Boas' men have not conceded a league goal, since being humbled by the Bundesliga club in Germany 2-0 - a result which took Leverkusen top of Group C with six points.
Zenit, however, are only two points back in third, and have enjoyed victories over Mordovia Saransk 5-0 and title challengers CSKA Moscow 1-0.
Leverkusen come into the fixture at Zenit's Stadio Petrovskij off a loss, humbled 1-0 by Hamburg on Saturday - their first league defeat in six.
Leverkusen left-back Wendell is unavailable for Roger Schmidt's men, after being sent off in their reverse fixture on October 22.
Midfielder Stefan Reinartz played 90 minutes against Zenit, but is embarking on a three-month layoff after incurring a fractured eye socket against Schalke.
Gonzalo Castro (thigh) and Rolfes (ankle) are further injury concerns for Schmidt.
Conversely, Villas-Boas was able to tinker with his outfit at the weekend, handing corner duties to forward Aleksandr Kerzhakov - a move the former Tottenham boss claimed dividends.
"We decided to do this after Kerzhakov had a very good corner against Arsenal that [Jose Salomon] Rondon also put in the goal," Villas-Boas told Zenit's website.
"So we worked on this during training, but we took this decision knowing that Kerzhakov has all the skills to make these corners work.
"Today one of his corners lead to a goal and for the first try, this is a really great result."
On the omission of Venezuelan forward Rondon, Villas-Boas insisted the 25-year-old was not on the outer.
"Well there were another 13 players that didn't play today too. We went with Kerzhakov and he played well," the Portuguese said.
"But we are talking with Rondon and he is training hard and knows that he will get his chance."
