The station was opened in 1862, together with the Czech Western Railway from Prague to Plzeň.

The current building of the Plzeň main railway station was opened in 1907.

Rudolf Štech also co-financed construction of the railway building and due to debt, he committed suicide in 1908.

On 17 April 1945, the building was heavily damaged during the bombing of Plzeň by the US Army Air Forces.

In the 1960s, the station was electrified as part of line electrification to České Budějovice.