Nablus came under the rule of the Ottoman Empire in 1517, along with the whole of Palestine. The Ottomans divided Palestine into six sanjaqs ("districts"): Safad, Jenin, Jerusalem, Gaza, Ajlun and Nablus. These six sanjaqs were subdistricts of the vilayet ("province") of Damascus. Sanjaq Nablus was further subdivided into five nahiya (subdistricts), in addition to the city itself. The Ottomans did not attempt to restructure the political configuration of the region on the local level such that the borders of the nahiya were drawn to coincide with the historic strongholds of certain families.
Nablus was only one among a number of local centers of power within Jabal Nablus, and its relations with the surrounding villages, such as Beita and Aqraba, were partially mediated by the rural-based chiefs of the nahiya. In 1522, a Jewish community settled in Nablus.
After decades of minor upheavals and rebellions mounted by some of the Arab tribes in the Middle East, the Ottomans attempted to reassert centralized control over the Arab vilayets.
In 1657, they sent an expeditionary force of local Ottoman-aligned Arab families based in various Syrian cities to pacify Nablus. In return for their services, the families were granted agricultural lands around the villages of Jabal Nablus.
The Ottomans, fearing that the new Arab land holders would establish independent bases of power, dispersed the land plots to separate and distant locations within Jabal Nablus to avoid clusters of clans. The 1657 campaign succeeded and the Syrian Arab families began to have a foothold in Nablus' affairs. The largest family were the Nimrs, who originated from villages surrounding Hama and Hims. The other two prominent families were the Jarrars from Balqa and the Touqans from northern Syria. Eventually gaining the role of nahiya chiefs, they began intermarrying with local merchant and leading religious families. Thus, these new families were integrated into Nablus' population.
Under an arrangement in 1723, the Touqans and the Nimrs would share and trade leadership of Nablus, and the Jarrars would indisputably become the chiefs of the nahiya of Jabal Nablus. In the mid-1700s, Dhaher al-Omar, an Arab native and ruler of the Galilee and Acre who was hostile toward Ottoman rule, rose to become the most dominant figure in northern Palestine. In order to build up his army, he strived to gain control over the cotton and olive oil trade of the Levant, which Jabal Nablus fueled. In 1771, during a Mamluk invasion of Syria, al-Omar aligned himself with the Mamluks, allowing him to temporarily besiege Nablus without gaining ultimate control over the city. In 1773, he led his army to besiege Nablus again, but to no avail. Nevertheless, from a political perspective, the sieges succeeded in raising Acre's prominence at the expense of Nablus. Al-Omar's successor, Jezzar Pasha, maintained Acre's dominance over Nablus.
After his reign ended in 1804, Nablus regained its original autonomy, and the Touqans, who represented a principal opposing force to Acre's dominance over Nablus, rose to power.