The history of Şanlıurfa is recorded from the 4th century BC, but may date back to 9000 BC, when there is ample evidence for the surrounding sites at Duru, Harran and Nevali Cori. It was one of several cities in the Euphrates-Tigris basin, the cradle of the Mesopotamian civilization. According to Turkish Muslim traditions Urfa (its name since Byzantine days) is the biblical city of Ur of the Chaldees, due to its proximity to the biblical village of Harran. However, based on historical and archaeological evidence, the city of Ur is today generally known to have been in southern Iraq, and the true birthplace of Abraham is still in question. Urfa is also known as the birthplace of Job.

For the Armenians, Urfa is considered a holy place since it is believed that Armenian alphabet was invented there.

Urfa was conquered repeatedly throughout history, and has been dominated by many civilizations, including the Ebla, Akkadians, Sumerians, Babylonians, Hittites, Armenians, Hurri-Mitannis (Armeno-Aryans), Assyrians, Chaldeans, Medes, Persians, Macedonians (under Alexander the Great), Seleucids, Arameans, Osrhoenes, Romans, Sassanids, Byzantines, and Crusaders.