The hosts are currently embroiled in a relegation battle in the second tier, whereas Dusseldorf are looking to hunt down the top three as they seek promotion this season.
Match preview
Since relegation from the Bundesliga in the 2018-19 campaign, Nuremberg have never looked like returning to the top flight of German football - to the massive disappointment of their loyal supporters.
Promotion is not even on the cards this campaign, with Markus Weinzierl's side currently 16th in the league standings, a position that would mean a relegation playoff at the end of the season.
Nuremberg have lost both of their league matches since returning from the World Cup - those two 1-0 defeats to St Pauli and Greuther Furth.
Weinzierl's men have found the DFB-Pokal to be a welcome distraction this season - albeit a very rare distraction - with Die Legende beating third-tier Waldhof Mannheim in the last round of the competition.
Wednesday's visitors Fortuna have more of a recent history with the Bundesliga, and also a greater chance of reaching those heights once again in the near future, with Dusseldorf currently sixth in the second tier.
However, Daniel Thioune and his men coming into this cup clash off the back of their heaviest defeat of the season, losing 4-1 to promotion-chasing Paderborn on Friday night at Home Deluxe Arena.
Rouwen Hennings's fourth goal of the season was merely a consolation for Fortuna on the night, and they will now look to get back to winning ways against a Nuremberg side who are struggling at the wrong end of the table.
Dusseldorf managed to win this competition twice in the 1970s and remarkably reached the final in three successive years between 1978 and 1980 - how fans would want a return to those glory days when they competed for the biggest honours in German football on a regular basis.
Nuremberg DFB-Pokal form:
W
W
Nuremberg form (all competitions):
D
L
D
W
L
L
Fortuna Dusseldorf DFB-Pokal form:
W
W
Fortuna Dusseldorf form (all competitions):
W
L
L
L
W
L
Team News
Nuremberg will be without goalkeeper Christian Mathenia for Wednesday's cup tie after the 30-year-old sustained a shoulder injury last month, meaning Dane Peter Vindahl Jensen will start between the sticks.
The hosts also have a pair of cruciate ligament injuries, with Erik Wesser and Tim Handwerker sidelined until September and April respectively, absences that limit Thioune's options at left-back.
Fortuna are hopeful midfielder Marcel Sobottka will be available for Wednesday after the 28-year-old suffered with a cold over the past week.
The visitors will definitely be without Kwadwo Baah unfortunately, with the attacker still around a week away from action after sustaining a hip injury in January.
Nuremberg possible starting lineup:
Jensen; Gyamerah, Hubner, Schindler, Nurnberger; Castrop, Tempelmann, Flick, Daehli; Nischalke, Duah
Fortuna Dusseldorf possible starting lineup:
Kastenmeier; Oberdorf, Hoffman, De Wijs, Karbownik; Hendrix, Tanaka, Klaus, Appelkamp, Peterson; Hennings
We say: Nuremberg 0-1 Fortuna Dusseldorf
Nuremberg have home advantage in this last-16 tie but have been woeful in front of their home faithful in Bundesliga 2 this season, winning just three of their nine home matches.