The Bundesliga side currently lead the pool going into the final round of the competition's group phase, with a place in the last 16 already assured.
Despite losing 1-0 at home to Monaco in their last Champions League outing, Roger Schmidt's men sit a point ahead of the Ligue 1 side, who will go head-to-head with Zenit for the right to join Leverkusen in next round.
Leverkusen - and particularly their captain Simon Rolfes - will be keen to ensure the best draw possible in the knockout phase, with the 32-year-old to bow out of football at the end of the season.
After Saturday's 1-0 defeat to Bayern Munich, the 32-year-old revealed his plans to move into an advisory role once his current contract expires in June and sporting director at the BayArena Rudi Voller thinks the club need to make the most of his experience while they still can.
He said: "Simon provides our young team with solidity and structure thanks to his experience and quality.
"And in the early stage of this campaign he was one of our best and most important players and we're glad he's available again following his serious injury.
"He could definitely play for another season or two at the top level. Even though he will go his own way in a couple of months, all the doors will be open to him."
Tuesday's hosts Benfica go into the match guaranteed to finish bottom of Group C, with third-placed Zenit holding a three-point advantage and better head-to-head record over Jorge Jesus' men.
Last season's UEFA Europa League runners-up have won only once in the Champions League this season, beating Monaco 1-0 at Estadio da Luz in November, with the Portuguese side having just four points to show for their efforts.
And Jesus has suggested that he will make a host of changes for their final European fixture of the season with Sunday's subsequent crucial Primeira Liga trip to Porto looming.
He told reporters: "Let's face the game with the utmost respect. No longer do we have the chance of qualification, but financial compensation is at stake.
"But, more importantly, on Sunday [we play against Porto] at [Estadio do] Dragao. And in the face of this game we will make many changes."
Benfica are expected to be without both Silvio (leg) and Eliseu (toe) for Leverkusen's visit, while Luisao and Andreas Samaris are both suspended.
Kyriakos Papadopoulos (shoulder) and Stefan Reinartz (cheekbone) will miss out for the visitors, with Giulio Donati (shoulder) doubtful.
