The founder of the city was Sames, was King of Sophene who made it his capital, after whom the city is named. The city is often confused with Arsamosata. Located in southeast Turkey on the upper Euphrates River, it was fortified so as to protect a major crossing point of the river on the east-west trade route. It also served as a station on another route running from Damascus, Palmyra, and Sura up to Lesser Armenia and the Euxine (Black) Sea. For a time, the city was called Antiochia in Commagene (Greek: Αντιόχεια η Κομμαγηνή). As Antiochia in Commagene, it served as the capital for the Hellenistic kingdom of Commagene from circa 160 BC until it was surrendered to Rome in 72. A civil metropolis from the days of Emperor Hadrian, Samosata was the home of the Legio VI Ferrata and later Legio XVI Flavia Firma, and the terminus of several military roads.
Samosata was the birthplace of Lucian (c. 120-192), a famous comic writer of antiquity, whose Trips to the Moon is sometimes called the first space novel, as well as 80 works which have survived to this day.
In the Christian martyrology, seven Christian martyrs were crucified in 297 in Samosata for refusing to perform a pagan rite in celebration of the victory of Maximian over the Persians: Abibus, Hipparchus, James, Lollian, Paragnus, Philotheus, and Romanus. Saint Daniel the Stylite was born in a village near Samosata; Saint Rabulas, venerated on 19 February, who lived in the sixth century at Constantinople, was also a native of Samosata. A Notitia Episcopatuum of Antioch in the sixth century mentions Samosata as an autocephalous metropolis (Echos d'Orient, X, 144); at the synod that reinstated Patriarch Photius I of Constantinople (the Photian Council) of 879, the See of Samosata had already been united to that of Amida (Diyarbakır). As in 586 the titular of Amida bears only this title it must be concluded that the union took place between the seventh and the ninth centuries. Earlier bishops included Peperius, who attended the Council of Nicaea (325); Saint Eusebius of Samosata, a great opponent of the Arians, killed by an Arian woman (c. 380), honoured on 22 June; Andrew, a vigorous opponent of Cyril of Alexandria and of the Council of Ephesus. Chabot gives a list of twenty-eight Jacobite bishops.
In February, 1098, the emir Baldoukh (Bulduk) of the Turkish Artukid or Ortoqid (Artuklu) dynasty, attacked by Baudouin of Antioch, cut his army to pieces there. In 1114 it was one of the chief quarters of the Muslims hostile to the Count of Edessa, to whom it succumbed, but was recaptured by the Muslims about 1149.