The Mongol Great Khan, Möngke, issued a directive to his brother Hulagu to extend the realms of the empire to the Nile River. The latter raised an army of 120,000 and in 1258, sacked Baghdad and slaughtered its inhabitants, including Caliph al-Musta'sim and most of his family. An-Nasir Yusuf sent a delegation to Hulagu afterward, repeating his protestations to submission. Hulagu refused to accept the terms and so an-Nasir Yusuf called on Cairo for aid. Aleppo was soon besieged within a week and in January 1260 it fell to the Mongols. The destruction of Aleppo caused panic in Muslim Syria. Damascus capitulated after the arrival of the Mongol army, but was not sacked like other captured Muslim cities. The Mongols proceeded by conquering Samaria, killing most of the Ayyubid garrison in Nablus, and then advanced south, as far as Gaza, unhindered. An-Nasir Yusuf was soon captured by the Mongols and used to persuade the garrison at Ajlun to capitulate.;

On 3 September 1260, the Egypt-based Mamluk army led by Qutuz and Baibars challenged Mongol authority and decisively defeated their forces in the Battle of Ain Jalut, outside of Zir'in in the Jezreel Valley. Five days later, the Mamluks took Damascus and within a month, most of Syria was in Bahri Mamluk hands. Meanwhile, an-Nasir Yusuf was killed in captivity.