Finds in Tell Dülük include stone tools from 30-40 thousand years ago. These tools are from a Neolithic culture, unofficially dubbed the "Dulicien culture" by researchers.
During the Hittite period, it was a stop on the road connecting the Mediterranean to Mesopotamia. It was also a religious center. The sanctuary of the Hittite god Teshub was just to the north of the village.
In the literary sources, the existence of the hellenistic colony is not attested before the 2nd century BC. It is speculated that part of the original colonial population of Doliche came from the homonymous Thessalian city. The discovery of Rhodean amphorea handles suggest communications with the Aegean Sea during the 3rd and 2nd centuries BC. The Seleucids adopted the worship of the local storm-god as Zeus Dolichenus, identified with Baal. At this time it was a small city on the road from Germanicia to Zeugma.
Doliche was at one time considered to belong to the ancient region of Cyrrhestica. It was ruled by the Kingdom of Commagene "for about 35 years"; after being governed by Antiochus Theos, it might have been incorporated into the Roman province of Syria as early as 31 BCE.
The worship of Jupiter Dolichenus became widespread from the mid-second to the mid-third century CE, particularly though not exclusively in the Roman army. A number of religious monuments of Jupiter Dolichenus refer to him as the "god of the Commagenians".
Doliche struck its own coins from the reign of Marcus Aurelius to Caracalla. Archaeological finds in Doliche include an underground Mithraic temple, rock graves and stone quarries from which giant rock blocks are produced.
In 2014, a team of German archaeologists from the University of Münster announced the excavation of a relief depicting an Iron Age deity previously unknown to them on a stele among the remains of Mar Solomon, a medieval monastery uncovered during 2010 excavations in Doliche. The monastery had been known only through writings indicating that it had been used through the era of the crusades. The University of Münster's Asia Minor Research Centre has been conducting excavation work at the main sanctuary of Jupiter Dolichenus under the direction of Engelbert Winter and Michael Blömer and is supported by the German Research Foundation (Deutsche Forschungsgesellschaft, DFG). The international group consists of archaeologists, historians, architects, conservators, archaeozoologists, geoinformation scientists, and excavation workers. Winter's field work at the sanctuary dates back to 2001.
In the middle of the 10th century, it played a role in the conflict between resurgent Byzantium and the Hamdanid emirate of Sayf al-Dawla, and was retaken by the Byzantines in 962. The town again became a battleground during the Crusades until it was definitely captured by atabegNur al-Din of Aleppo in 1155; by that time, it had declined to obscurity, its fortress in ruins and the once prosperous town reduced to a small village.
During the Crusades, the town was called Tulupa, and part of the Crusader County of Edessa.