The visitors are fourth in the second tier heading into the meeting, so they may feel confident of causing a major upset.
Match preview
Union Berlin continue to go from strength to strength under Urs Fischer, having opened up a four-point lead at the top of the Bundesliga by beating Borussia Dortmund 2-0 on Sunday.
BVB's goalkeeper Gregor Kobel had a nightmare moment by slipping on the ball in the eighth minute, allowing Janik Haberer to pounce and break the deadlock, before the midfielder beat Kobel from distance 15 minutes later to provide his side with an unassailable lead.
Only four teams across Europe's big five divisions boast a better defensive record than Union Berlin so far this season, meaning that they are not a team any side wants to fall behind to, particularly away from home.
As such, Fischer will be urging his side to dampen Heidenheim's spirits as early as possible at Stadion An der Alten Forsterei on Wednesday, as they look to build on last season's run to the DFB-Pokal semi-finals when they were eliminated 2-1 by eventual champions RB Leipzig.
Heidenheim, meanwhile, have made two appearances in the DFB-Pokal quarter-finals in recent seasons, when they were beaten by Hertha Berlin in 2015-16 and Bayern Munich in 2018-19.
They are still yet to gain promotion to the Bundesliga for the first time in the club's history but they are clearly knocking on the door under Frank Schmidt, who has been in charge since 2007, having finished sixth in the second tier last season.
Schmidt has guided his side to 20 points from their 12 league games this season, which puts them within five points of the three promotion places on offer and clearly in contention to reach the promised land come the end of the campaign.
Should they remain competitive against the most in-form team in the country on Wednesday, then that can only increase their belief of breaking the club's historical absence from Germany's top flight, although their trip to the capital essentially resembles a free hit for them.
Union Berlin DFB-Pokal form:
W
Union Berlin form (all competitions):
W
L
W
W
W
W
Heidenheim DFB-Pokal form:
W
Heidenheim form (all competitions):
W
D
D
D
W
L
Team News
Union Berlin appear to have no injury or suspension absences heading into Wednesday's encounter, allowing Fischer to rotate as much as he wishes to ahead of important league and European fixtures.
As such, the likes of Morten Thorsby, Sven Michel and Niko Griesselmann should start having been on the bench against Dortmund, but Andras Schafer is likely to retain his place as he is banned for next week's important home match against Braga in the Europa League.
Heidenheim, meanwhile, may travel without midfielder Jan Schoppner due to an ankle injury.
Tim Kleindienst is set to lead the line for the visitors, having bagged five goals in 12 appearances this season.
Union Berlin possible starting lineup:
Ronnow; Baumgartl, Doekhi, Jaeckel; Puchacz, Schafer, Seguin, Mohwald, Griesselmann; Michel, Behrens
Heidenheim possible starting lineup:
Muller; Busch, Mainka, Siersleben, Fohrenbach; Sessa, Thomalla, Maloney, Beck, Beste; Kleindienst
We say: Union Berlin 1-0 Heidenheim
Should Fischer significantly rotate his starting XI, which would not be surprising given that they are competing on three fronts this season, Heidenheim may push their opponents all of the way.
However, Union Berlin generally remain defensively resolute regardless of the personnel within their back five, and we expect no different on Wednesday.