The station opened in 1900. Serres was annexed by Greece on 18 October 1912 during the First Balkan War. On 17 October 1925, The Greek government purchased the Greek sections of the former Salonica Monastir railway^[3] and the railway became part of the Hellenic State Railways, with the remaining section north of Florina seeded to Yugoslavia. In 1970 OSE became the legal successor to the SEK, taking over responsibilities for most of Greece's rail infrastructure. On 1 January 1971, the station and most of Greek rail infrastructure were transferred to the Hellenic Railways Organisation S.A., a state-owned corporation. Freight traffic declined sharply when the state-imposed monopoly of OSE for the transport of agricultural products and fertilisers ended in the early 1990s. Many small stations of the network with little passenger traffic were closed down.

In 2001 the infrastructure element of OSE was created, known as GAIAOSE; it would henceforth be responsible for the maintenance of stations, bridges and other elements of the network, as well as the leasing and the sale of railway assists.^[4] In 2003, OSE launched "Proastiakos SA", as a subsidiary to serve the operation of the suburban network in the urban complex of Athens during the 2004 Olympic Games. In 2005, TrainOSE was created as a brand within OSE to concentrate on rail services and passenger interface.

On 9 September 2007, the station reopened. In 2008, all Proastiakos services were transferred from OSE to TrainOSE. In 2009, with the Greek debt crisis unfolding OSE's Management was forced to reduce services across the network. Timetables were cut back and routes closed as the government-run entity attempted to reduce overheads. Services from Thessaloniki and Alexandroupolis were cut back from six to just two trains a day, reducing the reliability of services and passenger numbers. In 2017 OSE's passenger transport sector was privatised as TrainOSE, currently, a wholly-owned subsidiary of Ferrovie dello Stato Italiane^[5] infrastructure, including stations, remained under the control of OSE. Since 2020, the station has been served by the Proastiakos Thessaloniki services to New Railway Station. In July 2022, the station began being served by Hellenic Train, the rebranded TranOSE^[6]

The station is still housed in the original 20th-century brick-built station building. As of (2020) the station is and slightly rundown.^[7] It is unstaffed. There is no footbridge over the lines, though passengers can walk across the rails and not wheelchair accessible. The station is equipped with digital display screens or timetable poster boards. There is a cafe/restaurant.

It is served by two long-distance trains between Thessaloniki and Alexandroupolis. Proastiakos service terminates here, with stopping services to New Thessaloniki.^[8]

Between July 2005 and February 2011, the Friendship Express, (an international InterCity train jointly operated by the Turkish State Railways (TCDD) and TrainOSE linking Istanbul's Sirkeci Terminal, Turkey and Thessaloniki, Greece) made scheduled stops at Serres.