It flourished as one of the largest localities in Palestine and one of the two market towns of the Safed Sanjak under Ottoman rule in the 16th century, when its population was mostly Muslim with a significant Jewish minority.

By the 19th century, its population was roughly equal parts Muslim and Christian, a state which persisted through British Mandatory rule (1917–1948).

In 2001, remains of a 4th-century BCE pottery kiln that produced everted rim storage jars were found adjacent to the Kanna spring.

[9] On the outskirts of the modern town is the tomb of the Jewish sage, rabbi Simeon ben Gamliel, who became the Nasi (president) of the Sanhedrin in 50 CE.

[10][11] Excavation beneath Kafr Kanna's Franciscan church uncovered mosaic floor panels with Aramaic donor inscriptions, using the square Jewish script.

Excavations under the same church also unearthed a round "discus" lamp dating from the second century AD, which includes a signature of the potter, named Iason.

[13] During excavations at Kerem er-Ras/Karm er-Ras, located on the western periphery of the village of Kafr Kanna, a fragment of a Latin burial inscription was discovered in 2001.

[14] Also unearthed in Kafr Kanna is a magic amulet from the 5th to 7th century, including a metal inscribed charm with 41 lines of Aramaic using the Jewish script.

[15][16][17] The Persian traveler Nasir-i-Khusraw visited the village in 1047 CE and described the place in his diary: To the southward [of Kafar Kannah] is a hill, on the top of which they have built a fine monastery.

[18]During the Crusader period, the Persian traveler Ali of Herat wrote that one could see the Maqam of Jonas, and also the grave of his son, at Kafr Kanna.

[18] Al-Dimashqi further remarked that the waters of the surrounding hills drained into the area, flooding it; as soon as the land was dried up grain was sown.

[21] Under the rule of the Ottoman Empire, the village flourished in the 16th century, as it lay on the western trade route between Egypt and Syria.

[29] A map from Napoleon's invasion of 1799 by Pierre Jacotin showed the place, named as Cana,[30] and David Roberts' The Holy Land, Syria, Idumea, Arabia, Egypt, and Nubia illustrated the same in two separate lithographs.

[41] On July 22, 1948, the two priests, Giuseppe Leombruni (Catholic) and Prochoros (Greek Orthodox), and the Christian mayor surrendered Kafr Kanna peacefully to the advancing Haganah troops, ensuring that the population could remain in the village.

On 30 March 1976, a resident of Kafr Kanna, Muhammad Yusuf Taha, was one of six people killed by the Israeli army during Land Day demonstrations.

However, the general view starting from the 12th-century placed Cana at Khirbet Kana, a site 8.5 kilometres (5.3 mi) to the northwest of Kafr Kanna.