[4] Strategically located at a crossroads on the western bank of the Euphrates and considered the key to Syria from Iraq, control of the town was highly contested by the Muslim powers and Bedouin tribes of the region.

In the early 20th century, Mayadin was the administrative seat of the Asharah kaza (subdistrict) of the Sanjak of Zor district and contained the residence of its qaimmaqam (governor).

[7][8] In a British military intelligence report from the 1900s, the town had a population of 2,000 mostly Sunni Muslims and a small minority of Christians.

[7] On June 19, 1947, Pan Am Flight 121, crewed by third officer Gene Roddenberry (who went on to create the original Star Trek television series), crashed 4 miles (6.4 km) from the town.

The only part still in regime hands was the Mayadin military base, an artillery position on a hill overlooking the town,[9] which was captured on 22 November.

[11] A local underground resistance movement of Sunni Muslim fighters loyal to the al-Nusra Front attacked ISIL checkpoints in the city in 2015.

[14] On 21 April 2017, the United States announced that they had conducted a ground raid in Mayadin and killed Abdulrakhman Uzbeki, an ISIS leader.