Nearby localities include Tadmur (Palmyra) to the northeast, Furqlus to the north, al-Riqama and Dardaghan to the northwest, Mahin, Huwwarin and Sadad to the west, Qarah, Deir Atiyah and al-Nabk to the southwest and Jayrud to the south.

During Roman rule, it served as a popular health resort,[4] and a base for the legionary cavalry unit "Equites Promoti Indigenae".

[9] During Abd al-Malik's reign over the Umayyad Caliphate (646–705), his son al-Walid I used al-Qaryatayn along with adjacent towns in the area as a base of operations.

[11] In late 1104, the Seljuk prince (emir) Suqman ibn Artuq died in the town on his way to Damascus after being summoned by the ruler of that city, Zahir ad-Din Tughtekin.

[12] Arab geographer Yaqut al-Hamawi visited al-Qaryatayn in the early 13th century and described it as "a large village belonging to Hims, and on the desert road.

[15] In the middle part of that century, during the reign of the Egyptian governor of Syria, Ibrahim Pasha, al-Qaryatayn was a small village with mud brick homes.

[19] At the time of Musil's visit, al-Qaryatayn's sheikh was Ahmad ibn Fayyad Agha, and the village paid numerous regional Bedouin tribes, including the Ruwalla, Wuld Ali, Sba'a, and Fad'an, the annual khuwwa ('brotherhood') tribute as a means to either protect them from their plundering raids or to return goods stolen from the inhabitants by individual members of those tribes.

This situation was a result of the weakness of al-Qaryatayn's sheikh, which was in contrast to his father, Fayyad Agha ibn Da'as (died 1903), under whom no tribe disturbed the village.

[25][26] ISIL later advanced even further, taking control of Mahin and Huwwarin by 8 August, thus forcing hundreds of Christians to flee persecution by the terrorist group.

[27] On 9 August 2015, the Syrian Arab Air Force (SAAF) bombed Islamic State of Iraq and the Levant positions in al-Qaryatayn, resulting in the death of around 30 militants as well as the destruction of seven vehicles and a rocket depot, according to government sources.