The Bundesliga leaders got past SV Sandhausen in the previous round, while their second-tier visitors upset Freiburg to reach this stage.
Bayer Leverkusen head into the DFB-Pokal round of 16 on the back of an eye-catching start to the 2023-24 season on all fronts under Xabi Alonso's management, having gone unbeaten in their 20 games across all competitions thus far.
As a result, Die Werkself sit atop the Bundesliga table after 13 outings with 35 points on the board, with their only two draws this term coming in Germany's top flight, while also leading their Europa League group with a perfect record from five outings, guaranteeing a spot in the knockout stage as a result.
Their cup campaign began with a trip to Teutonia Ottensen in the first round in August, and Alonso's men progressed in style with an 8-0 beating, as Adam Hlozek netted a brace alongside goals from Edmond Tapsoba, Victor Boniface, Florian Wirtz, Amine Adli, Jeremie Frimpong and Jonas Hofmann, setting up a second-round tie away at third-tier SV Sandhausen.
After twice going ahead through Exequiel Palacios and Jonathan Tah, Die Werkself were pegged back and had to wait until the 85th minute to regain a lead through Hlozek, before Adli netted a late brace to seal a 5-2 victory in what was a tougher test than the final scoreline suggested.
Having returned from the November international break in similarly strong form to beforehand, starting with triumphs away at Werder Bremen and Hacken to extend a winning run to 14 matches before most recently taking a creditable point from a 1-1 draw against Borussia Dortmund thanks to a Boniface equaliser, Bayer Leverkusen will now aim to return to winning ways on Wednesday to book their place in the DFB-Pokal quarter-finals and strengthen their hopes of winning silverware in what has been a particularly impressive campaign thus far.
In their way stand an SC Paderborn side who will aim to pull off another cup upset on Wednesday and reach their first DFB-Pokal quarter-final since the 2018-19 season.
Lukas Kwasniok's side began with a trip to fourth-tier Energie Cottbus, and they advanced in similar style to Wednesday's hosts with a 7-0 thrashing, as Filip Bilbija hit a brace alongside a Dominik Pelivan own goal and goals from Visar Musliu, Florent Muslija, Sebastian Klaas and Mattes Hansen.
That set up a tough trip to Bundesliga outfit Freiburg in the second round at the beginning of November, and the second-tier visitors defied the odds to prevail in dominant fashion, eventually winning 3-1 having seen out a two-goal lead after initially going 3-1 up at the Europa-Park Stadion through another Bilbija and a Muslija goal.
Now on the back of an important return to winning ways in what has been a disappointing 2. Bundesliga campaign thus far, as Muslija netted the only goal in injury time in a 1-0 triumph over 10-man Hannover 96 to fire his side up to 10th spot after 15 games, Paderborn will aim to make it back-to-back triumphs on Wednesday and score a memorable victory at the BayArena to keep their cup run alive.
Bayer Leverkusen will likely remain without defender Arthur through injury, although forward Patrik Schick did return to contention and featured off the bench after his own fitness concern.
The Czech international may come in to lead the line from the outset on Wednesday should Alonso opt to make some rotations and afford a rest for star forward Victor Boniface, with Amine Adli also vying to come in from the outset after his own substitute appearance at the weekend.
Likewise, Nathan Tella and Adam Hlozek will fight for starts in the front three after Jonas Hofmann and Florian Wirtz joined Boniface last time out, while Robert Andrich may come in to join Granit Xhaka in the engine room with Jonathan Tah, Odilon Kossounou and Edmond Tapsoba expected to line up in an unchanged back three.
SC Paderborn will travel to the BayArena with a similar starting XI from the weekend's 1-0 victory over Hannover 96, and Filip Bilbija will continue to play a key role in attack having netted four goals in their two DFB-Pokal outings so far this term.
He could again join Moritz Flotho and Ilyas Ansah in attack, while Florent Muslija is another danger man having already notched up nine goals alongside four assists in 16 appearances in all competitions this season.
Bayer Leverkusen possible starting lineup:
Hradecky; Kossounou, Tah, Tapsoba; Frimpong, Andrich, Xhaka, Grimaldo; Hlozek, Schick, Adli
SC Paderborn possible starting lineup:
Boevink; Curda, Rohr, Hoffmeier; Obermair, Klefisch, Hansen, Muslija; Bilbija, Flotho, Ansah
We say: Bayer Leverkusen 3-0 SC Paderborn
SC Paderborn pulled off a major upset on their travels in the second round, but we do not see them managing the same again against a Bayer Leverkusen side who are yet to lose a competitive game this term.
Even with rotations anticipated, Alonso's men should certainly have the quality to progress to the quarter-finals on home turf.
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