Between 1258 and 1291, the region faced turmoil as the frontier between Mongol invaders, occasionally allied with Crusaders, and the Mamluks of Egypt. This conflict led to significant population reduction and economic hardship. The Mamluks were mostly of Turkish origin, and were bought as children and then trained in warfare. They were highly prized warriors, who gave rulers independence of the native aristocracy. In Egypt they took control of the kingdom following a failed invasion by the Crusaders (Seventh Crusade).

The Mamluks took control in Egypt and expanded their rule to Palestine. The first Mamluk Sultan, Qutuz, defeated the Mongols at the Battle of Ain Jalut, but was assassinated by Baibars, who succeeded him and eliminated most Crusader outposts. The Mamluks ruled Palestine until 1516, regarding it as part of Syria. In Hebron, Jews faced restrictions at the Cave of the Patriarchs, a significant site in Judaism, a limitation that persisted until the Six Days War.^[146]

Al-Ashraf Khalil, a Mamluk sultan, captured the last Crusader stronghold in 1291. The Mamluks, continuing Ayyubid policies, strategically destroyed coastal regions from Tyre to Gaza to prevent potential Crusader sea attacks. This devastation led to long-term depopulation and economic decline in these areas.^[147]

The Jewish community in Palestine saw rejuvenation with the influx of Sephardic Jews following their expulsion from Spain in 1492 and persecution in Portugal in 1497. Under Mamluk and later Ottoman rule, these Sephardic Jews predominantly settled in urban areas like Safed and Jerusalem, contrasting with the mostly rural Musta'arbi Jewish community.^[148]