Bayer Leverkusen, Wolfsburg and Hamburg all need points to be sure of avoiding relegation, while Mainz, Augsburg and Ingolstadt hope to beat them to it.
One of the six will go down automatically - Darmstadt are already relegated - while a relegation playoff offers a second chance for another against the side that finishes third in the German second division.
All Bundesliga games take place at the same time during the final two rounds of the campaign.
Second-bottom Ingolstadt, who play at Freiburg on Saturday, are the worst placed side, four points from safety and ruing Kai Havertz's late equaliser for Leverkusen in their 1-1 draw last weekend.
But Ingolstadt coach Maik Walpurgis isn't giving up.
"The Bundesliga has already written so many crazy stories. Why not this year, too?" Walpurgis said.
Hamburg, currently on 34 points are in the playoff place, play at Schalke before a potential all-or-nothing meeting against Wolfsburg at home on the final weekend.
Hamburg, the only founding member of the league to have played every season in the top flight, are facing the prospect of a third playoff in four seasons.
Schalke, 41 points, have only theoretical chances of salvaging a European place but will be compelled to put on a good performance in front of their own frustrated fans.
Mainz, level with Hamburg, host local rivals Eintracht Frankfurt in a derby between the two worst sides in the second half of the season.
Frankfurt's best chance of European qualification is by winning the German Cup final against Borussia Dortmund.
Wolfsburg, the 2009 German champions, host Borussia Moenchengladbach, who are led by their former coach Dieter Hecking.
Hecking was fired after a poor start by Wolfsburg in October. Andries Jonker is the Volkswagen-backed club's third coach of the season.
"We've given away the season," Wolfsburg striker Mario Gomez said.
Augsburg were the prime candidate for the drop but carved some breathing space with wins over Cologne and Hamburg, though former player Andre Hahn's late equaliser for 'Gladbach in last weekend's draw may yet prove decisive.
Augsburg host Borussia Dortmund on Saturday, when the visitors will be hoping to consolidate third place for automatic Champions League qualification at Hoffenheim's expense.
Dortmund are two points ahead of Hoffenheim, who visit Werder Bremen.
Bremen are pushing for a European place after a remarkable recovery in the second half of the season.
Leverkusen, who were playing Champions League soccer this season, appear to be in the worst shape of all the relegation rivals after six games without a win under new coach Tayfun Korkut.
It could get worse for Leverkusen with defeat at home to European hopefuls Cologne in the Rhine derby on Saturday.
Cologne fans are taking particular "schadenfreude" in seeing their old rivals struggle, particularly as Leverkusen was widely seen as a title-contender before the season began.
Sixth-place Hertha Berlin are in danger of ending the season with nothing after nine straight losses away from home. The team have a chance to end that run at already-relegated Darmstadt.
Bayern Munich, who wrapped up their fifth straight title with three games to spare, host promoted Leipzig in a battle between two teams assured of direct qualification for the Champions League.