Zippori is mentioned in many Jewish sources of the first centuries. The Zippori Jews did not join the revolt against Rome in 66 C.E.; instead, they opened the city gates to the legions of the Roman Emperor Vespasian and surrendered. On coins minted in Zippori at that time, the city is named Eirenopolis, "city of peace."

The Jewish community grew when thousands of refugees from Judea moved to towns in the Galilee following the Bar-Kokhba revolt of 135 and Zippori became the center of Jewish religious and spiritual life in the Land of Israel. Rabbi Yehuda Hanasi, who relocated the Sanhedrin (the supreme Jewish religious and judicial body he headed) to Zippori in the third century. At least 18 synagogues were functioning in the city around this time and Jews constituted the majority of the town's population.

Even after the seat of the Sanhedrin was moved to Tiberias, Zippori remained a center of Bible study and notable sages taught in its numerous academies. Zippori thrived with it’s location on or near major trade routes in the lower Galilee, made Zippori a prime market for traders.

The discovery of rich, figurative mosaics during excavations at Zippori provide evidence of the Roman character of the city's pagan population, which coexisted in harmony with the Jews during the period of economic prosperity in the late Roman period. Zippori was destroyed in 363 by an earthquake, but was rebuilt soon thereafter, retaining its social and spiritual centrality in Jewish life in the Galilee.

The city is also the traditional birthplace of Mary and just four miles of Nazareth, the home of Jesus. During Byzantine times, the Christian community in Zippori grew considerably. This growth was accompanied by the construction of many churches and by Christian involvement in municipal matters. It became the seat of a Christian bishopric in the 5th century CE. Following the Arab conquest in the mid-seventh century, the city declined.