Both embroiled in a battle to avoid the drop, the home side could leapfrog their capital city visitors with a win but return to Rhein-Neckar-Arena having lost their seventh game in a row.
Match preview
Amid speculation that Hoffenheim head honcho Dietmar Hopp plans to remove coach Pellegrino Matarazzo from his position should the ex-Stuttgart boss fail to end the club's losing run this week, plenty is riding on Saturday's fixture.
After failing to pick up a point in the American's five Bundesliga matches in charge, such a 'six-pointer' could prove crucial in his quest to keep Die Kraichgauer afloat in Germany's top flight and retain his current job.
Hoffenheim's 2-1 loss to Freiburg last week extended their winless streak to its 14th game, leaving them bottom of the pile for the first time since 2016 and also occupying one of two automatic relegation places - a far cry from pre-season expectations.
Seven successive league defeats represents a new club record, and they are just the second Bundesliga team ever to lose their first seven fixtures in the second half of a season; only Angelo Stiller's strike at Freiburg prevented them going four games without a goal.
However, history will be on their side when Hertha arrive in Sinsheim, as Hoffenheim have not beaten any current Bundesliga club more often at home; indeed, they have only lost one of the teams' last eight meetings at Rhein-Neckar-Arena.
Remarkably, Hoffenheim were fourth in the table going into October's reverse fixture, when they took the lead through Andrej Kramaric before Dodi Lukebakio grabbed an equaliser for Hertha just before half time.
That draw brought one of a meagre 21 points for the capital club this season, and they were last worse off at this stage of a top-flight campaign in 2010.
After their 1-1 home draw against Mainz last week, the Berliners have actually claimed seven points from their last five outings - as many as from their previous 11 - and are now outside the Bundesliga drop zone by the skin of their teeth.
Sandro Schwarz's side join Hoffenheim as one of five teams separated by just three points at the wrong end of the standings, so while there is still all to play for, the stakes are particularly high this weekend.
Considering Die Alte Dame's dire away form, even an ailing home side may fancy their chances against them on Saturday afternoon, as Hertha have lost each of their last seven away games in the league - their longest such run since the 2016-17 campaign.
In fact, with just four points gleaned from 11 road trips to date, they possess the worst away record in the Bundesliga this season, but they will find few better opportunities to improve it.
Hoffenheim Bundesliga form:
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Hertha Berlin Bundesliga form:
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Team News
Though Sebastian Rudy hopes to return from a thigh injury and Kasper Dolberg could be back in contention after suffering a concussion, Hoffenheim will still have Jacob Bruun Larsen (groin) and Grischa Promel (ankle) sidelined on Saturday.
In addition, Ozan Kabak serves his third Bundesliga suspension of the season and must be replaced in defence, though Christoph Baumgartner returns from a ban and should start further forward.
Most likely beginning the game on the bench, Andrej Kramaric has notched 10 league goals against Hertha in the past and scored in the 1-1 draw in Berlin this season. However, he is on a six-game goal drought and was an unused substitute versus Freiburg.
The visitors, meanwhile, are missing Jean-Paul Boetius, Chidera Ejuke and Kelian Nsona, but veteran striker Stevan Jovetic recently returned following a long absence and has made cameo appearances in each of Hertha's last three matches.
Jessic Ngankam should still start up front, though, having scored from the spot last weekend, with top scorer Dodi Lukebakio likely to join Jovetic on the bench.
Hoffenheim possible starting lineup:
Baumann; Kaderabek, Brooks, Akpoguma; Skov, Stiller, Geiger, Angelino; Baumgartner; Bebou, Dabbur
Hertha Berlin possible starting lineup:
Christensen; Uremovic, Kempf, Dardai; Richter, Cigerci, Tousart, Serdar, Plattenhardt; Niederlechner, Ngankam