Founded under the auspices of the Roman emperor Vespasian in 72 CE and originally named Flavia Neapolis, the city prospered in particular because of its strategic site and the abundance of nearby springs. Later called Julia Neapolis, or simply Neapolis (Greek: “New City”), it is portrayed on the 6th-century Maʾdabā map (see Maʾdabā (Madabā)). It was conquered by the Arabs in 636 CE; the modern name is an Arabic corruption of the Greek form. The city was held by the Crusaders from 1099 until 1187; they called it Naples, and it was briefly the Crusader capital.

The city site of Nāblus is not identical to the site of the ancient Canaanite city of Shechem, although the two have long been associated with one another. Shechem, an important city in ancient Palestine, was noted in particular for its position between Mount Gerizim (Gerizim, Mount) and Mount Ebal (Arabic: Jabal al-Ṭūr and Jabal ʿAybāl, respectively) in an east-west pass, one of the few such routes in Palestine's hill country. The two cities have been closely (though erroneously) linked for almost 2,000 years: both rabbinic and early Christian literature commonly equated Nāblus with ancient Shechem, and Nāblus has been called Shekhem in Hebrew to the present. Ruins of the Canaanite city lie at Tall al-Balāṭah, to the east of the present city of Nāblus; these show evidence of settlement from the Middle Bronze II period (c. 1900–c. 1750 BCE).

Nāblus has been a largely Muslim Arab city for centuries, though it is also the principal centre of the small Samaritan community. In modern times Nāblus was part of the British mandate of Palestine (1920–48); taken by Arab forces in the first of the Arab-Israeli wars in 1948–49, it was subsequently annexed by Jordan. A principal centre of Arab opposition both to Britain and to the Zionist movement during the mandate, it was the scene of frequent unrest, and from 1948 to 1967 Nāblus was a centre of guerrilla operations directed against Israel. Resistance activities continued after the Six-Day War of 1967 and the subsequent Israeli occupation of the city, but by the early 1970s the situation had tempered. After the Yom Kippur War of October 1973, Nāblus once again became a centre of Arab opposition to the occupying forces. In the wake of the 1993 Oslo Accords, Nāblus was evacuated by Israeli forces, and the city came under the control of the Palestinian Authority.

Nāblus's economy was traditionally based on agricultural trade and handicrafts—most notably, the important and long-established industry of manufacturing soap from olive oil. It became a centre of industry and commerce in modern times. A number of educational facilities are centred in Nāblus. Al-Najaḥ National University (1977) offers courses of study in a range of fields; courses are primarily taught in Arabic, although English is the language of instruction for the sciences. The Nāblus Municipality Public Library, also situated in the city, houses primarily Arabic and English volumes. Among Nāblus's notable cultural sites are the Jāmiʿ al-Kabīr and Jāmiʿ al-Nasr mosques, which are built on the remains of Byzantine churches; the old Samaritan quarter; and the traditional site of Jacob's Well, south of the city. Pop. (2005 est.) 130,300.