Begun in 1835, it was opened from the Potsdam end as far as Zehlendorf on 22 September 1838, and its entire length of 26 km on 29 October.

Five major streets eventually converged here, most having started out as mere rough tracks through the Tiergarten park and adjoining fields.

The first Potsdamer Bahnhof lasted until 1869, when it was superseded by a far grander structure in response to growing traffic, built by Julius Ludwig Quassowski (1824–1909) with five platforms, a trainshed roof that was 173m long and 36m wide, a booking hall with separate waiting rooms and facilities for four classes of ticket holders, and a separate entrance and reception area on the west side for visiting royalty.

Opened on 30 August 1872, it eventually handled train services to and from Cologne, Paris, Frankfurt/Main, Strasbourg and Aix en Provence.

Originally using 550 V DC, it was converted to 800 V in April 1929, in the course of the "Grand Electrification" of the core of Berlin's city, Ring, and suburban lines.

Under the grand plan by Adolf Hitler, to transform Berlin into the Welthauptstadt (World Capital) Germania, to be realised by Albert Speer, the building would have ceased to be a railway terminus.

The new North-South Axis, the linchpin of the plan, would have severed its approach tracks, leaving the terminus stranded on the wrong side of it.

Despite some rubble clearance and emergency repairs, damage to rail infrastructure further out was so great that the mainline terminus never saw another train, it and the Ringbahnhof finally closed on 3 August 1944.

The Ringbahnhof closed for good on 27 July 1946 after some fragmentary train workings had resumed along the U-Bahn and North-South Tunnel on 2 June.

The East German regime decided to leave the site of the Potsdamer Bahnhof outside of the wall, although it remained formally and legally part of the Soviet Sector until 21 December 1971, when East Germany were paid DM 31 million for this piece of land as part of a wider land swap.

Where the Potsdamer Bahnhof once stood is a long landscaped strip of land named after the Austrian actress Tilla Durieux (1880–1971), stretching for 450 m down to the Landwehrkanal.

Deutsche Bahn have apparently ordered another operational replica in time for the 175th anniversary celebrations in 2010, for the Nuremberg - Fürth railway line, Germany's first.