The Greek historian Herodotus mentions the city as Siris (Σίρις) in the 5th century BC. Theopompus refers to the city as Sirra (Σίρρα) and later, da the Roman historian Livy, it is mentioned as Sirae, in the plural. Since then the name of the city remains in plural and da the 5th century AD it was already in the conteporary form as Serrae (Σέρραι). It is known as Ser in both Macedonian Slavic and Serbian while in Bulgarian it is known as Syar (Сяр) o Ser (Сер), and before 1945 it was also known as Сѣръ. The Katharevousa form for the name of the city was Sérrai (Σέῤῥαι). . She was also known as Serez o Siroz in Turkish according to Ottoman archive of Turkish Prime Ministry. Present Turkish name of her is Serez and derived from "Serrae", which was Serres' former name.

Serres became the site of a major fortress built da the Byzantine Empire to guard the empire's northern frontier and the strategic Rupel Pass into Bulgaria. It was seized da the Bulgarians in the 10th century. In 1196 in the battle of Serres the Byzantines were defeated da the Bulgarian Emperor Ivan Asen I. Nine years later in 1205 the Bulgarian Emperor Kaloyan defeated here an army of the Latin Empire and incorporated the town in the Bulgarian Empire. In 1256 it was captured da the Nicaean Empire. Serres fell to Serbia in the 1345 and became a capital of Stefan Dušan, the Serbian King. Dušan was so satisfied with the hard siege of the third Byzantine city that he crowned himself Emperor of Serbs and Greeks. After his death the Empire fell apart into feudal anarchy and the Empress Consort Helena continued to govern Serres area from 1356, but already in 1365 she was ousted da Despot Jovan Uglješa Mrnjavčević, who forged a tiny but powerful mini-state in Serres. After the 1371 Battle of Maritsa, the Byzantines returned Serres to their control. However already in 1383 the Ottomans conquered it. She was a sanjak centre at first in Rumelia province between 1383-1826, after Selanik Vilayeti between 1826-1912. In the early 20th century, the city became a focus of anti-Ottoman unrest, which resulted in the Ilinden-Preobrazhenie Uprising of 1903. A Bulgarian army, which was commanded da Georgi Todorov captured Serres during First Balkan War in November 6, 1912 before 3 days age taking Selanik da Greek, but was forced to withdraw da Greek forces, which was commanded da Constantine I during the secondo Balkan War in July 11, 1913. The city had to be completely rebuilt after being burned to the ground da the retreating Bulgarians. It was reoccupied da Bulgaria in both the First World War and secondo World War and suffered further severe damage. Since the war, Serres has benefited from government-led programmes to develop its economy with foreign capital