Long used as a Hittite port which appears in Hittite sources as "Sinuwa" (J. Garstang, The Hittite Empire, p. 74), the city proper was re-founded as a Greek colony from the city of Miletus in the 7th century BC (Xenophon, Anabasis 6.1.15; Diodorus Siculus 14.31.2; Strabo 12.545). Sinope flourished as the Black Sea port of a caravan route that led from the upper Euphrates valley (Herodotus 1.72; 2.34), issued its own coinage, founded colonies, and gave its name to a red arsenic sulfate mined in Cappadocia, called "Sinopic red earth" (Miltos Sinôpikê) or sinople. It escaped Persian domination until the early 4th century BC, and in 183 BC it was captured by Pharnakes I and became capital of the kingdom of Pontus. Lucullus conquered Sinope for Rome in 70 BC, and Julius Caesar established a Roman colony there, Colonia Julia Felix, in 47 BC. Mithradates Eupator was born and buried at Sinope, and it was the birthplace of Diogenes, of Diphilos, poet and actor of the New Attic comedy, of the historian Baton, and of the Christian heretic of the 2nd century AD, Marcion.

It remained with the Empire of the East or the Byzantines. It was a part of the Empire of Trebizond from the sacking of Constantinople by the Fourth Crusade in 1204 until the capture of the city by the Seljuk Turks of Rüm in 1214.

In 1301, Sinop became an independent emirate following the fall of the Seljuks. See Candaroglu. It was captured by the Ottomans in 1458.

In November 1853, at the start of the Crimean War, in the Battle of Sinop, the Russians, under the command of admiral Nakhimov, destroyed an Ottoman frigate squadron in Sinop, leading Britain and France to declare war on Russia.