The settlement existed and developed in antiquity and in the 3rd century BC, under the name of Antigoneia. It was founded by the Macedonian king Antigonus 2nd Gonat, in the period between 278–242 BC. After conquering Paionia, he conquered the settlements around the central Vardar region. In his name, the settlement that he founded was called Antigoneia.
The material data and the legends say that Antigoneia, predecessor of Negotino, was situated 12 Roman miles south from the antique town Stobi, on the road to Thessaloniki, at today's place of Gradiste, by the railway station of Negotino. At this place, coins with faces of Roman emperors were found, as well as precious jewelry and other archeological findings from the period of the Roman and Byzantine period.
The ancient town existed until the 11th century when it was destroyed by a disastrous earthquake which hit almost all of the territory of Macedonia along with other towns, such as Scupi, Stobi, Heraklea and Astibo. During the middle ages, Negotino was part of the empire of Samuil.
Its name appears for the first time as a name of a Turkish ciflik (manor) at the beginning of the 19th century. At this time, by the Tair-aga Sinan, the Clock Tower was built, which is one of the famous monuments of the town is the Clock Tower, which suffered the great fire in 1913.