At the beginning of the 3rd century, Rabbi Yehudah Ha-Nassi and the Sanhedrin were in Saffuriyya (Sepphoris) until the middle of the third century, until its transfer to Tiberius. During his residence in  Saffuriyya (Sepphoris),  Ha-Nassi compiled and edited the Mishnah, the first major collection of rabbinical legal rules and the core of the Talmud.

In 324 A.D, the Emperor Constantine declared Christianity the official state religion - a step which marks the beginning of the Byzantine period. He supported a Jewish convert named Joseph, granted him the title of Friend of the Caesar (Lat. Comes), and permitted him to build a church in Saffuriyya (Sepphoris). The city's Christian community grew considerably and many churches were constructed. Sepphoris rose to the status of a bishopric.

In 351 C.E., a revolt broke out in Saffuriyya (Sepphoris) against Gallus Casear, Governor of the Syrian Province. Ursicinus, the Chief of Cavalry, put down the uprising but did not destroy the city.

Only a dozen years later, however, Palestine was rocked by an extremely violent earthquake, and Saffuriyya (Sepphoris)was completely laid waste - although it was very quickly restored and rebuilt.

Saffuriyya had a resident bishop in the 4^th century CE.

In 518 C.E, A church, dedicated it to Anne and Joachim, was bult in their house.