Elsewhere, Bayer Leverkusen, Wolfsburg and Borussia Monchengladbach will fight for the last remaining UEFA Champions League qualification slot as Robert Lewandowski and Mario Mandzukic compete to finish top of the scoring charts.
While each of their fellow 15 co-founders have succumbed to relegation since the Bundesliga's 1963 inception – maiden champions Cologne being the last in 1998 – Hamburg have never gone into the final day sweating over their status.
But Mirko Slomka's side sit third bottom, just one point above Nuremburg with Eintracht Braunschweig a further point back.
One of the trio will go into a play-off for a place in the 2014-15 Bundesliga – almost certainly against Greuther Furth – while demotion will befall the other two.
Nuremberg must attempt to end a run of six straight defeats by winning at third-placed Schalke for the first time in 21 years, while Braunschweig – winless and goalless in four outings – visit free-scoring Hoffenheim.
A number of people within German football have expressed their desire to see Hamburg, founded in 1887 and known as 'The Dinosaur', survive.
"I hope they can avoid relegation," Pep Guardiola said of the 1982-83 European Cup winners. "A club with so much history belongs in the Bundesliga."
Guardiola's runaway champions Bayern Munich, who beat Hamburg 4-1 last time out, are at home to fourth-bottom Stuttgart.
Thomas Muller could make his 200th league appearance – and potentially his last for Bayern – while Mandzukic will hope to boost his chances of finishing as the competition's leading marksman.
Lewandowski's last league game for Dortmund is away to mid-table Hertha Berlin.
