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Zeugma started its existence as a Greek town, founded by Seleucus I Nicator, one of the Diadochi, the friends of Alexander the Great who fought for control over his empire after his death in 323 BCE. In ancient times, the name Zeugma encompassed the twin cities, perching on both banks of the Euphrates. The western town was also known as Seleucia after the founder, while the eastern settlement was called Apamea as Seleucus' Persian wife name was Apama.

Zeugma was incorporated into the Roman Empire in 64 BCE and soon gained importance as a commercial centre with its geo-strategic location on the Silk Road. It was also situated at the eastern border of the empire while the Persian Empire occupied the vast lands to the east of Euphrates. Interestingly, Marcus Crassus crossed the Euphrates in Zeugma, on his ill-fated campaign against the Parthians.

During the first two centuries of the first millennium CE, Zeugma was also the military base of Legio IV Scythica. Soldiers, officers, and high-ranking officials of the Roman Empire significantly contributed to the city's development and prosperity

The city was invaded and destroyed by its eastern neighbours in 256 CE when the Sassanid king, Shapur I, attacked it. A massive earthquake helped to put an end to Zeugma's wealth and affluence, and the city never restored its previous prosperity. During the early Eastern Roman Empire period, Zeugma was still inhabited. Procopius mentions that Emperor Justinian built a wall around the city and strongly fortified it. Zeugma was abandoned in the 7th century because of the Arab raids.