The name of the city in Roman and early Byzantine times was Callicum or Callicus (Greek: Καλλικών, Καλλικώς) and was later known as Kalkis or Kilkis.

Findings dating back to as early as the Bronze and Iron Age have been excavated in the vicinity of Kilkis, including ancient tombs of the 2nd millennium BC.

In late antiquity the area of Kilkis saw invasions of different tribes, such as the Goths, the Huns, the Avars and the Slavs, some of whom gradually settled in the Balkan Peninsula.

In the 10th century, it was sacked by the Bulgarians, and some of the inhabitants moved to Calabria, in southern Italy, where they founded the village of Gallicianò.

[citation needed] During the reign of the Palaeologus dynasty, the region saw the completion of a number of important infrastructure works.

[citation needed] In 1840–1872 the intellectuals Dimitar Miladinov, Andronik Yosifchev, Rayko Zhinzifov and Kuzman Shapkarev were teachers in the local school.

An 1873 Ottoman study concluded that the population of Kilkis consisted of 1,170 households, of which there were 5,235 Bulgarian inhabitants, 155 Muslims and 40 Romani people.

A catalogue of native Macedonians who participated in the Macedonian Struggle ("Greek armed struggle for Macedonia") during 1904–1908 lists five persons originating from Kilkis: Georgios Samaras, Ioannis Doiranlis and Petros Koukidis, who were members of armed bands, and Evangelia Traianou-Tzoukou and Ekaterini Stampouli, as "agents of third order".

The Chatziapostolou family owned a great farm in Metalliko, the field crop of which was almost completely given to fund the Greek efforts.

In the Second Balkan War of 1913, the Greek army captured the city from the Bulgarians after the three-day Battle of Kilkis-Lahanas between 19 and 21 June.

Kilkis was set on fire and almost completely destroyed by the Greek Army after the battle[21][22] and virtually all of its 13,000[23] pre-war Bulgarian inhabitants were expelled to Bulgaria.

In the mid-1920s, after the Asia Minor Catastrophe, waves of refugees came to Kilkis, thus giving a new boost to the region and contributing to the increase of its population.

The most significant event during the occupation was the Battle of Kilkis which took place on 4 November 1944 between the communist-led EAM and a coalition of the collaborationist Security Battalions and nationalist resistance organizations.

The Kilkis is served by KTEL Bus, which performs daily trips to/from Athens, Thessaloniki and other cities within Greece.