The area has been inhabited as far back as it is possible to discover. Research in the cave of Palanli 10 km north of Adiyaman and other digs in Samsat reveal continuous occupation through the stone and Bronze Ages.

From 900BC onwards came waves of invasions from Assyrians, Persians, and Macedonians until the Greco-Iranian Commagene kingdom was founded in 69BC. This was the civilisation that built the statues on top of nearby Mount Nemrut. The capital was in Samsat (Samosata) but the town of Adiyaman was a walled city of the Commagenes. The city walls of Adiyaman have been restored and replaced many times since.

The Commagene kingdom lasted until the Romans came in 72AD. Yet more campaigns and invasions followed and Adiyaman was controlled by Byzantines 395-670, Ummayads from 670 and then Abbasids 758-926. Then the area returned to Byzantine control during 859-1114. The Arabs returned from 1114 to 1204 and finally came the arrival of the Turks. The Arabic name for the castle and town was Hisn-i Mansur.

Turks moved into the area from 1114 onwards and for most of the 13th century was settled by the Selçuk Turks often disrupted by Mongol invasions. From 1298 to 1516 the town was under the control of the Mameluks. Adiyaman was brought into the Ottoman Empire by Selim I in 1516, but local power often rested with the Dulkadirogullari tribe of Turkmen people that settled here.

There is some passing tourist trade, the main tourist attraction being Mount Nemrut.

The caves of Pirin (ancient city of Perre) are 5 km (3 mi). from Adiyaman. These have been used as a burial ground for thousands of years. The sights include the ruins of the city and burial caves carved into the rock.

The only active church in Adiyaman Province is located here, where it is the center of the Syriac Orthodox patriarchal vicarate of Adiyaman. It was renovated and reopened in 2012.

The River Euphrates runs through the province just south of the city and the massive Attaturk Dam has created an enormous lake system extending over an area of 817 km² (315 sq mi) with a water volume of 48.7 km³ (63,400 million cu yd). Built both to generate electricity and to irrigate the plains in the region, it was renamed in honour of Mustafa Kemal Atatürk (1881-1938), the founder of the Turkish Republic.