Alexander camped in the highlands of İskenderun, around Esentepe, and then ordered the city to be established and named Alexandria.

İskenderun is one of many cities founded on Alexander’s orders, including Alexandria, Egypt. A memorial, a monument and a bronze statue for the victory raised at the city, and Herodian writes that they were there even at his time.

The importance of the place comes from its relation to the Syrian Gates, the easiest approach to the open ground of Hatay Province and Aleppo.

The bishopric of Alexandria Minor was a suffragan of Anazarbus, the capital and so also the ecclesiastical metropolis of the Roman province of Cilicia Secunda. Greek menologia speak of Saint Helenus, and the martyr saints Aristio and Theodore as early bishops of the See. But the first documented one is Hesychius, who took part in the First Council of Nicaea in 325 and in a synod at Antioch in 341. Philomusus participated in the First Council of Constantinople in 381. Baranes is mentioned in connection with a synod at Antioch in 445. At the Council of Chalcedon in 451, Julianus was represented by his metropolitan, Cyrus of Anazarbus. Basilius was at the synod in Constantinople in 459 that condemned simoniacs. In 518, Paulus was deposed by the Byzantine Emperor Justinian for supporting the Jacobite Severus of Antioch.

At the outset of World War I, when Britain was contemplating the partition of the Ottoman Empire, Lord Kitchener considered the conquest of Alexandretta to be essential in providing Britain with a port and railhead from which to access Iraq. He proposed a new railway be built to the east from Alexandretta, which would greatly reduce the time for reaching India from the UK. The De Bunsen Committee (8 April – 30 June 1915), a British inter-departmental group which was set up to discuss the issue in greater detail, preferred Haifa for this purpose.

Republic of Hatay
Following the collapse of the Ottoman Empire at the end of the First World War, most of Hatay including İskenderun was occupied by French troops.

In July 1920 the San Remo conference did not assign Alexandretta sanjak to Turkey. Between 1921 and 1937, the city was part of the autonomous Sanjak of Alexandretta within French-controlled Syria, under the League of Nations French Mandate of Syria and the Lebanon.

The Republic of Hatay was founded in 1938 and, in 1939, it joined the Republic of Turkey after a referendum. The referendum was, and still is, regarded as illegitimate, as the Turkish government moved supporters into the city and the Turkish Army “expelled most of the province’s Alawite Arabs, Greek and Armenian majority” to decide the referendum result.