Until World War I, trains ran from the German capital via Königsberg to Saint Petersburg (Nord Express) and to Moscow as well as to Vienna, Budapest, and Constantinople via Breslau and Kattowitz.

During the Anti-Jewish pogroms in the Russian Empire, numerous Jewish refugees arrived here to travel on to the emigration harbors in Hamburg and Bremerhaven.

The station was severely damaged by strategic bombing during World War II and had to be completely rebuilt by the East German railway, the Deutsche Reichsbahn.

In 1950 it was renamed Berlin Ostbahnhof, as upon the implementation of the Oder–Neisse line, the former Silesia province was now largely a part of Poland, and its German population expelled.

A partially built staircase to the underground car park from this period in front of the station remains (in 2006) unfinished and fenced off.

In the film, Jason Bourne (Matt Damon) is seen parking his car here, entering the station and leaving a bag in a locker, and tracking down Pamela Landy (Joan Allen).