Leverkusen are aiming to recover from a disappointing 1-1 draw with Schalke, whereas Koln suffered a 2-1 home defeat to Union Berlin last time out.
Peter Bosz's side would have been confident of picking up all three points when they travelled an out-of-sorts Schalke side, but Leverkusen could only manage a 1-1 draw with David Wagner's men on Sunday evening.
Schalke were very much the victims of their own downfall as Juan Miranda's own goal cancelled out Daniele Caligiuri's penalty, but that point was enough for Leverkusen to overtake Borussia Monchengladbach into the fourth and final Champions League spot.
Bosz's side now sit on 57 points - one ahead of Monchengladbach following their defeat to champions-elect Bayern Munich, and the Leverkusen faithful will be optimistic about their side's chances of maintaining their top-four standing with their final three fixtures all against teams in the bottom half of the table.
Die Werkself also have a DFB-Pokal final against Bayern to look forward to following their comfortable 3-0 semi-final win over fourth-tier side Saarbrucken, but as for now, Bosz will be aiming to avoid a third consecutive home defeat for his side in the German top flight.
In contrast, Koln suffered their third defeat in four at the weekend as Union Berlin ended their winless run with a 2-1 victory in Koln's backyard.
Markus Gisdol's side now lie in 12th without a victory since the restart, but Koln's strong performances earlier in the campaign should be enough for them to cement their position in the Bundesliga for another season.
Indeed, the Billy Goats are seven points clear of the relegation zone prior to the final two weeks of the season, but Gisdol will no doubt be determined to get three points on the board for his own peace of mind.
Nevertheless, Koln have to be wary of Union Berlin and Augsburg both picking up victories at the weekend, and they are now only ahead of both sides on goal difference.
Gisdol's side can move up to 11th with a win should Hertha Berlin suffer defeat against Freiburg the day before, and there is every reason for Koln fans to be hopeful as the Billy Goats enjoyed a 2-0 victory over Leverkusen back in December.
Bayer Leverkusen Bundesliga form: WWLWLD
Bayer Leverkusen form (all competitions): WLWLWD
Koln Bundesliga form: DDLLDL
Leon Bailey missed out at the weekend for the birth of his son, although the 22-year-old is expected to return for Wednesday's fixture.
Bayer Leverkusen possible starting lineup:
Hradecky; Weiser, Tah, S. Bender, Wendell; Baumgartlinger, Aranguiz; Amiri, Havertz, Bailey; Volland
Koln possible starting lineup:
Horn; Ehizibue, Bornauw, Czichos, Schmitz; Hector, Skhiri; Drexler, Uth, Jakobs; Cordoba
We say: Bayer Leverkusen 2-0 FC Koln
Leverkusen will be desperate to avoid any more slip ups as the race for the final Champions League spot hots up, and we expect the DFB-Pokal finalists to record a straightforward victory over a Koln side who are winless in seven matches.