[5] Safed has been identified with Sepph (Σέπφ), a fortified town in the Upper Galilee mentioned in the writings of the Roman Jewish historian Josephus.

After reverting to the Crusaders in a treaty in 1240, a larger fortress was erected, which was expanded and reinforced in 1268 by the Mamluk sultan Baybars, who developed Safed into a major town and the capital of a new province spanning the Galilee.

Safed's population reached 24,000 toward the end of the 19th century; it was a mixed city, divided roughly equally between Jews and Muslims with a small Christian community.

Its Muslim merchants played a key role as middlemen in the grain trade between the local farmers and the traders of Acre, while the Ottomans promoted the city as a center of Sunni jurisprudence.

Safed's conditions improved considerably in the late 19th century, a municipal council was established along with a number of banks, though the city's jurisdiction was limited to the Upper Galilee.

Since the place was conquered by Al Malik Adh Dhahir [Baybars] from the Franks [Crusaders], it has been made the central station for the troops who guard all the coast-towns of that district.

[56] The extant parts of the work consisted of ten folios largely devoted to Safed's distinguishing qualities, its dependent villages, agriculture, trade and geography, with no information about its history.

[58] He noted Safed lacked "regular urban planning", madrasas (schools of Islamic law), ribats (hostels for military volunteers) and defensive walls, and that its houses were clustered in disarray and its streets were not distinguishable from its squares.

[44] There is little available information about the city and its dependencies during the last century of Mamluk rule (c. 1418 – c. 1516), though travelers' accounts describe a general decline precipitated by famine, plagues, natural disasters and political instability.

Each quarter was named for the place of origin of its inhabitants: Purtuqal (Portugal), Qurtubah (Cordoba), Qastiliyah (Castille), Musta'rib (Jews of local, Arabic-speaking origin), Magharibah (northwestern Africa), Araghun ma' Qatalan (Aragon and Catalonia), Majar (Hungary), Puliah (Apulia), Qalabriyah (Calabria), Sibiliyah (Seville), Taliyan (Italian) and Alaman (German).

[77] After the expulsion of the Jews from Spain in 1492, many prominent rabbis found their way to Safed, among them the Kabbalists Isaac Luria and Moses ben Jacob Cordovero; Joseph Caro, the author of the Shulchan Aruch; and Solomon Alkabetz, composer of the Shabbat hymn "Lekha Dodi".

[44] In 1602, the paramount chief of the Druze in Mount Lebanon, Fakhr al-Din II of the Ma'n dynasty, was appointed the sanjak-bey (district governor) of Safed, in addition to his governorship of neighbouring Sidon-Beirut Sanjak to the north.

In the preceding years, the Safed Sanjak had entered a state of ruin and desolation and was often the scene of conflict between the local Druze and Shia Muslim peasants and the Ottoman authorities.

[85] He formed close relations with the city's Sunni Muslim ulama (religious scholars), particularly the mufti, al-Khalidi al-Safadi of the Hanafi school of fiqh (Islamic jurisprudence), who became his practical court historian.

[87] Fakhr al-Din returned to his domains in 1618 and five years later regained the governorship of Safed, which the Ma'n dynasty had lost, after his victory against the governor of Damascus at the Battle of Anjar.

[88] In c. 1625, the orientalist Franciscus Quaresmius spoke of Safed being inhabited "chiefly by Hebrews, who had their synagogues and schools, and for whose sustenance contributions were made by the Jews in other parts of the world.

[101] In the following year, the Muslim notables of the city, led by Salih al-Tarshihi, opposed to the Egyptian policy of conscription, joined the peasants' revolt in Palestine.

[106] Emir Bashir Shihab II of Mount Lebanon and his Druze fighters entered its environs in support of the Egyptians and compelled Safed's leaders to surrender.

[105] The Galilee earthquake of 1837 killed about half of Safed's 4,000-strong Jewish community,[107] destroyed all fourteen of its synagogues and prompted the flight of 600 Perushim for Jerusalem;[108] the surviving Sephardic and Hasidic Jews mostly remained.

In the new province, Safed remained part of the Acre Sanjak and served as the center of a kaza (third-level subdivision), whose jurisdiction covered the villages around the city and the subdistrict of Mount Meron (Jabal Jarmaq).

[111] The survey recorded a relatively high number of businesses in the city, namely 227 shops, fifteen mills, fourteen bakeries and four olive oil factories, an indicator of Safed's long-established role as an economic hub for the people of the Upper Galilee, the Hula Valley, the Golan Heights and parts of modern-day South Lebanon.

[116] In 1888 the Acre Sanjak, including the Safed Kaza, became part of the new province of Beirut Vilayet, an administrative state of affairs which persisted until the Empire's fall in 1918.

[116] The Ottomans developed Safed into a center for Sunni Islam to counterbalance the influence of non-Muslim communities in its environs and the Shia Muslims of Jabal Amil.

[133] The Palmach's Third Battalion failed to take the main objective, the "citadel", but "terrified" the Arab population sufficiently to prompt further flight, as well as urgent appeals for outside help and an effort to obtain a truce.

[11] Early in June, Jewish dignitaries from Safed journeyed to Tel Aviv to ask the government to block the return of Arabs to the city, threatening to abandon it if the latter were allowed back.

[143] The village of Akbara in the city's southwestern outskirts, which had a population of about 500 Arab Muslims, most of whom belonged to a single clan, the Halihal, is under Safed's municipal jurisdiction.

[152] It was created in order to allow haredi women living in the Upper Galilee access to higher education, while still maintaining strict religious practice.

[152] In October 2011, Israel's fifth medical school opened in Safed, housed in a renovated historic building in the centre of town that was once a branch of Hadassah Hospital.

For women, Sharei Bina is a midrasha (seminary) offering a one-year post high school program,[158] with an increased focus on Jewish spirituality - including formal study of Kabbalistic topics.

[169] The Citadel Hill, in Hebrew HaMetzuda, rises east of the Old City and is named after the huge Crusader and then Mamluk castle built there during the 12th and 13th centuries, which continued in use until being totally destroyed by the 1837 earthquake.