In 63 B.C. Palestine was conquered by the Roman army led by Pompey.

In 55 B.C.  Gabinius, provincial governor of Syria, made end to the Jewish political authority and declared Saffuriyya (Sepphoris) the capital of the Galilee District.

In 47 B.C Antipater, father of Herod the Great, was given Roman citizenship by Caesar, and was appointed provincial governor of Judea. Herod made his political debut the same year, as Governor of Galilee. Six years later, he was appointed ruler of Galilee.

In the civil war of 40 B.C, Herod fled to Rome, where he was named King of Judea by the Roman Senate. His actual reign began in 37 B.C, when he took back control of the country. Herod's army conquered Saffuriyya (Sepphoris) from Antigonus, the last Hasmonean king during a severe snowstorm.

Herod made Saffuriyya (Sepphoris) his base of operations in the north and it remained the Galilee capital all during his rule. He could well have used the old Seleucid fort to stockpile his weapons

In 4 b.c, Herod the Great died, Judas son of Hezekiah, led the Jews in a rebellion against Roman rule, Gaius sent by Quintilius Varus, Roman governor of Syrie, burned Saffuriyya  (Sepphoris).

However, the city seems to have recovered quickly. During the reign of Herod's son Herod Antipas, the city was rebuilt and restored to its former status as district capital. Flavius Josephus describes this city as the "ornament of all Galilee."

Saffuriyya (Sepphoris)  remained the capital of Galilee until about 18 A.C, when Herod Antipas constructed the new city of Tiberius on the Sea of Galilee and shifted his capital there.

In 37 A.C, after the death of Antipas, Herod Agrippa moved the capital of Galilee back to Saffuriyya (Sepphoris). Agrippa began an extensive building program of repair to make the move of the capital back acceptable, then renamed the city 'Autocratoris'.

In 66 A.C, the Great Jewish Rebellion against Rome broke out. The people of Saffuriyya (Sepphoris), however, signed a pact with the Roman army, thus averting the destruction of their city. Probably at this time it was renamed Eirenopolis Neronias ('Nero's City of Peace'), which appears on coins from 67 to 68 AD.

According to Josephus Saffuriyya (Sepphoris) was "the strongest city in Galilee." Nevertheless, at some point the city Elders appeared to have changed their minds. Rather than risk destruction, the inhabitants of Saffuriyya (Sepphoris) welcomed a garrison of Roman soldiers into the city, which was later joined by another contingent from the Roman general and future emperor Vespasian. The old fort, first used by the Seleucids and later by the Hasmoneans and Herod the Great, may have been filled in shortly before 68 A.C and made into a great open plaza as a sign of the city's good will and change of heart toward the Romans.

At the end of the first century A.C. and of the beginning of the second, amphitheater was built, and a new aqueduct system was constructed. This system served most of the needs of the city, as well as two public bathhouses in the lower city. An agora (marketplace) was probably also added. Coins bearing the bust of the emperor Trajan (98-117 AD) were minted by the city.

The role played by Saffuriyya (Sepphoris)  in the Bar Kokhba Revolt (132-135 A.C) is unclear, but the local leadership was ousted because of Jewish influence, and a non-jewish administration appointed. During that time its name was changed to Diocaesarea by Hadrian (117 -138) honoring both Zeus (in Latin, Dio) and the emperor (caesar). This was the name by which the city is known in pagan and Christian literature,

During 138-161 A.C The Roman emperor Antoninus Pius reigns. Coins minted in Saffuriyya (Sepphoris) during his rule not only bear the bust of the emperor but also display images of pagan deities and the new city name: Diocaesarea,.

In this period, the Jewish character of population started decreasing, since the days of Herod the Great, and the Greco-Roman influences become more as a result of good relations between the local inhabitants and the Romans, especially, they didn’t participate in Jewish rebellions          

The hellinization of Saffuriyya (Sepphoris) was significantly increased, it was clear in architectur, gymnasium, Forum ,amphitheater, and in the dressmaking.