The northern club is the only one to have played in the Bundesliga every season since the top league's creation in 1963 but it has fallen on hard times in recent seasons.
Despite repeated cash injections from investor Klaus-Michael Kuehne, Hamburg were narrowly saved in 2014 and 2015 and are again on 16th place, two points behind Wolfsburg.
A win would seen them climb into safety and leave the Wolves battle it out with the third-placed club from the second division over two relegation playoff legs.
But Hamburg will be without forward Pierre-Michel Lasogga, whose late equaliser last week against Schalke 04, kept them in them alive in the race for 15th spot.
The striker is out with an adductor muscle injury he picked up in training on Wednesday.
"We have carved out our chance now," said Hamburg coach Markus Gisdol ahead of their home game. "We have shown we are strong at home and now we have to throw everything we have in to this game."
"I expect an amazing atmosphere. The team must then start a fire and the fans will be behind us."Hamburg will have a two-day training camp ahead of the game in order for the players to focus and prepare for it.
"It was also a wish from the team itself to have this camp. We will have perfect conditions there," Gisdol said.
Wolfsburg, champions in 2009, will again count on forward Mario Gomez, who has 16 goals, to come to the rescue, with as point enough to keep them in the Bundesliga.
Borussia Dortmund will look to beat Werder Bremen and make sure they hold on to third place that leads to the Champions League group stage.
Dortmund are on 61 points, same as Hoffenheim, who have a worse goal difference and take on Augsburg, level with Wolfsburg on 37 points.
Champions Bayern will celebrate their record-extending fifth straight league title with a home game finale against promoted Freiburg, who are hoping to crown a sensational season with a Europa League spot.
(Editing by Amlan Chakraborty)
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