A sell-out crowd is expected at BWT-Stadion am Hardtwald, where the home fans suffered seeing their side relegated last time out, which is in stark contrast to their high-flying opponents.
Match preview
Indeed, Sandhausen's 11-year stay in the second tier of German football came to an end last season, as they finished rock-bottom with only 28 points from 34 matches.
After gaining promotion to Bundesliga 2 for the first time in the club's history in 2012, Sandhausen never finished higher than 10th across those ensuing 11 seasons, with 44 points being their highest points tally at that level. As such, it was no huge surprise to see them finally fall short of the mark.
The club's chairman Jurgen Machmeier changed managers on two occasions but to no avail, and he has already bit the bullet during the current campaign, having replaced Danny Galm with former Schalke 04 and Union Berlin boss Jens Keller last week.
Keller made a winning start with his side beating Borussia Dortmund's reserve team 2-1 away from home on Saturday, but the 52-year-old will be more than aware that his players will require a monumental effort to avoid defeat against the most in-form team in the country in midweek.
After all, only Bayern Munich have prevented Leverkusen from winning all 13 of their games in all competitions so far this season, with Xabi Alonso's side maintaining their status at the Bundesliga's summit with a 2-1 win against Freiburg on Sunday.
Florian Wirtz and Jonas Hofmann struck either side of half time to provide Die Werkself with a comfortable foothold at BayArena, but they had to resist some late pressure after Manuel Gulde pulled one back for the visitors with 20 minutes of normal time remaining.
Both sides appeared to be a little tired after claiming wins in the Europa League less than 72 hours prior to kicking-off, meaning that claiming three points was the only important thing. Another six points from a tricky trip to Hoffenheim before hosting struggling Union Berlin would ensure that Leverkusen remain top of the table heading into the international break in November.
In the meantime, though, the Spaniard will expect to see his side progress into the third round of the DFB-Pokal, while booking their place in the knockout stages of the Europa League, as the former Liverpool and Real Madrid midfielder looks to lift Leverkusen's first trophy since 1993.
SV Sandhausen DFB-Pokal form:
W
SV Sandhausen form (all competitions):
W
L
L
L
L
W
Bayer Leverkusen DFB-Pokal form:
W
Bayer Leverkusen form (all competitions):
W
W
W
W
W
W
Advert - content below:
Team News
Sandhausen will remain without defenders Lucas Laux, Luca Zander and Dennis Diekmeier due to injury, meaning that Christoph Ehlich may have to continue playing out of position at right-back.
With an important home game against Saarbrucken on Saturday, Keller may be tempted to make a few changes given the unlikelihood of his side winning this tie, but equally his strongest players will demand an opportunity to impress against one of the strongest teams in Germany.
Leverkusen, on the other hand, will almost certainly significantly rotate their starting XI given the importance of their away game against Hoffenheim three days later.
Patrik Schick is in need of a start after his recent injury woes, while Matej Kovar, Robert Andrich, Nadiem Amiri and Josip Stanisic will expect to start after being left on the bench against Freiburg.
However, Alonso will remain without the services of Ayman Aourir and Arthur due to serious tendon injuries.
SV Sandhausen possible starting lineup:
Rehnen; Ehlich, Geschwill, Fuchs, Weik; Muhling, Ben Balla; Stolze, Hennings, Maciejewski; Otto
Bayer Leverkusen possible starting lineup:
Kovar; Fosu-Mensah, Stanisic, Kossounou, Hincapie; Andrich, Amiri; Tella, Adli, Hlozek; Schick
We say: SV Sandhausen 0-2 Bayer Leverkusen
Sandhausen will hope to see their opponents make as many selection changes as Alonso is likely to, as this will clearly improve their chances of producing a shock result against Leverkusen.
However, the visitors have decent squad depth to call upon, with Schick possessing enough quality on his own to dispose of a third division team. Alonso's side are building momentum and we expect them to make it 13 wins from 14 games in all competitions for the campaign.