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.
Hamburg have lost their last four games, their last eight away, and have not kept a clean sheet in 12 matches. However, Slomka is optimistic he can record his 100th Bundesliga victory as a coach when he takes his team to UEFA Europa League-chasing Mainz.
Johan Djourou and key forward Pierre-Michel Lasogga have recovered from injuries, while Hamburg have lost just one of their seven trips to Mainz in the Bundesliga.
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.
The Croatia striker is level on 18 goals with Lewandowski, whom he will compete with for a place in the Bayern attack next season.
Lewandowski's last league game for Dortmund is away to mid-table Hertha Berlin.
Bayer Leverkusen are one point above Wolfsburg and two clear of Borussia Monchengladbach in the race for the fourth and final Champions League berth.
Leverkusen are at home to Werder Bremen, while Wolfsburg host Monchengladbach.
Augsburg will pip Mainz to the final Europa League spot if they win at home to Eintracht Frankfurt and Hamburg avoid defeat at the Coface Arena.
Finally, Hannover and Freiburg meet in a match of little importance.
