The ancient city of Zeugma was originally founded as a Greek settlement by Seleucus I Nicator, one of the generals of Alexander the Great, in 300 BC. King Seleucus almost certainly named the city Seleucia after himself; whether this city is, or can be, the city known as Seleucia on the Euphrates or Seleucia at the Zeugma is disputed. The population in the city at its peak was approximately 80,000.

In 64 BC Zeugma was conquered and ruled by the Roman Empire and with this shift the name of the city was changed into Zeugma, meaning "bridge-passage" or "bridge of boats". During Roman rule, the city became one of the attractions in the region, due to its commercial potential originating from its geo-strategic location because the city was on the Silk Road connecting Antioch to China with a quay or pontoon bridge across the river Euphrates.

In 256, Zeugma experienced an invasion and it was fully destroyed by the Sassanid king, Shapur I. The invasion was so dramatic that Zeugma was not able to recover for a long time. To make the situation even worse, a violent earthquake buried the city beneath rubble. Indeed, the city never gained the prosperity once achieved during the Roman rule.

In the 4th century, Zeugma and environs became a Late Roman territory. During the 5th and 6th centuries the city was ruled over by the Early Byzantium domination. As a result of the ongoing Arab raids the city was abandoned once again. Later on, in the 10th and 12th centuries a small Abbasid residence settled in Zeugma.