Ma'arrat al-Nu'man entered the nascent Muslim Empire when Abū 'Ubayda took the city in 637 CE/AH 16. During the early Islamic period, the city remained an economic center since it was located at the crossroads of several trade routes. Although it fell under the hands of several rulers, the only political event that negatively affected the town during this time was its capture by the Byzantine Emperor Nikephoros II Phokas in 968/357 AH, whose troops destroyed the town's great mosque. Byzantine occupation did not last long before the town was recaptured for Islam. In the middle of the eleventh/fifth century AH, the Iranian geographer Nasir-i Khusraw described the town as flourishing regional center.

In 1098/492 AH the city was taken by the Crusaders and although it's authority shifted back and forth, Zangī finally was able to reconquer it in 1135/529 AH. After passing out of Frankish into Zangid, then Ayyubid hands, the town was incorporated into the Mamluk Empire in 1341/742 AH. The town remained part of the Mamluk Empire for nearly 200 years until the battle of Marj Dabik in 1516/922 AH, when it was annexed into the Ottoman Empire, where it remained until the empire's dismemberment after the First World War.