This coast has been inhabited since the 9th millennium BC. Excavations by John Garstang of the hill of Yumuktepe have revealed 23 levels of occupation, the earliest dating from ca. 6300 BC. Fortifications were put up around 4500 BC, but the site appears to have been abandoned between 350 BC and 300 BC.
In subsequent centuries, the city became a part of many states and civilizations including the Hittites, Assyrians, Persians, Greeks, Seleucids and Lagids. During the Ancient Greek period, the city bore the nameZephyrion (Greek: Ζεφύριον) and was mentioned by numerous ancient authors. Apart from its natural harbor and strategic position along the trade routes of southern Anatolia, the city profited from trade inmolybdenum (white lead) from the neighbouring mines of Coreyra. Ancient sources attributed the best molybdenum to the city, which also minted its own coins.
The area later became a part of the Roman province of Cilicia, which had its capital at Tarsus, while nearby Mersin was the major port. The city, whose name was Latinized to Zephyrium, was renamed as Hadrianopolis in honor of the Roman emperor Hadrian.
After the death of the emperor Theodosius I in 395 and the subsequent permanent division of the Roman Empire, Mersin fell into what became the Byzantine Empire.
The city was an episcopal see under the Patriarchate of Antioch. Le Quien names four bishops of Zephyrium:Aerius, present at the First Council of Constantinople in 381; Zenobius, a Nestorian, the writer of a letter protesting the removal of Bishop Meletius ofMopsuestia by Patriarch John of Antioch (429–441); Hypatius, present at the Council of Chalcedon in 451; and Peter, at the Council in Trullo in 692. The bishopric is included in the Catholic Church’s list of titular sees, but since the Second Vatican Council no newtitular bishop of this Eastern see has been appointed.
The area of Cilicia was conquered by the Arabs in the early 7th century, by which time it appears it was a deserted site. After them came the Egyptian Tulunids, the Byzantines between 965 and the 12th century, the Armenian Kingdom of Cilicia, Mamluks, Anatolian beyliks, and finally the city was conquered by the Ottomans from the Ramadanid Principality in 1473 and formally annexed by Selim I in 1517.
During the American Civil War, the region became a major supplier of cotton to make up for the high demand due to shortage. Railroads were extended to Mersin in 1866 from where cotton was exported by sea, and the city developed into a major trade center.
In 1909, Mersin’s port hosted 645 steamships and 797,433 tons of goods. Before World War I, Mersin exported mainly sesame seeds, cottonseed, cakes and cereals, cotton, and livestock. Cotton was exported to Europe, grain to Turkey, and livestock to Egypt. Coal was the most prevalent import into Mersin at this time. Messageries Maritimes was the largest shipping line to use the port at Mersin.
In 1918, Mersin was occupied by French and British troops in accordance with the Treaty of Sevrès. It was recovered by the Turkish army in 1920. In 1924, Mersin was made a province, and in 1933 Mersin and İçel provinces were joined to form the (greater Mersin) İçel province.
As of 1920, Mersin had five piers at its port, with one privately owned by a railroad company serving Mersin, Tarsus, and Adana.