Halberstadt station was opened by the Magdeburg–Halberstadt Railway Company (Magdeburg-Halberstädter Eisenbahngesellschaft) on 21 March 1842.

The regional administration in Magdeburg granted a concession to the Magdeburg–Halberstadt Railway Company to extend the line on 26 November 1860.

Similarly, a new signal box was built to handle the increasing traffic as a result of line extensions to Halle (Saale) and between Wernigerode and Bad Harzburg.

Further extensions occurred between 1904 and 1908, when two new humps, a water tower and the Wehrstedt bridge were built.

It had two depots for locomotives, a repair shop, an express freight office and several sidings connecting to local companies.

The commander of a special train operated by the Wehrmacht that was standing in the station forced its locomotive crew to depart from the station, contrary to the general instructions, which indicated that an ammunition train standing at the siding could not be hauled onto the open field of tracks during an air raid.

When one of the ammunition train's anti-aircraft guns opened fire, the station was hit by US Air Force fighter-bombers.

After the gasometer exploded, the ammunition train was also hit, destroying the station, the offices and adjoining residential and industrial buildings.

During a second raid on 8 April, the western station area, including the repair shop, and the eastern exit was severely hit.

A total of 45 locomotives and hundreds of passenger carriages and freight wagons were destroyed and 80% of the track infrastructure was no longer usable.

Until signal boxes Hr1 and HR2 had been restored in 1952, the points had to be set manually using hand switches or keys.

Trains from Halberstadt ran to the west only to Wernigerode and Stapelburg as the connection over the inner-German border to Vienenburg had been dismantled.

Trains from Halberstadt ran to the west only as far as Wernigerode and Stapelburg as the connection over the inner-German border to Vienenburg had been dismantled.

From 1968 to 1970, the entrance building received a curtain wall made of corrugated iron on the occasion of the 20th anniversary of the GDR.

Due to the corrugated iron wall, the station was often called the Sardinendose (sardine can) in Halberstadt.

The building was acquired in 2008 by NOSA GmbH, a holding company owned by the town of Halberstadt.

Only Alstom Coradia LINT diesel multiple units (class 1648) have been used since 9 December 2018.

In the timetable for 2025, Halberstadt Hauptbahnhof was served by the following services: Two tram lines, two bus routes and a night bus route, which runs to the main districts from 20:00 to about 22:30, are operated by Halberstädter Verkehrs-GmbH (the municipal transport company), stopping in the station forecourt.

In addition, southeast of the station is the bus station, from which nine regional bus lines and four demand-responsive services are operated by Harzer Verkehrsbetriebe, the transport company of the Harz district.