Palestine was conquered by Alexander the Great in 332 B.C.

In 200 BC  Seleucid ruler Antiochus III   conquered Jerusalem. Saffuriyya (Sepphoris) becaome the site of a Seleucid fort constructed by either Antiochus III or his successor, Antiochus IV. The fort bolsters the city's reputation as a key stronghold in Galilee.

In 168 BC, the Jewish, led by  Hasmonaeans, revolted  against Seleucid Greek king Antiochus IV.

After their victory in Jerusalem, In 163 BC, they had a political independence,

in 142 BC.  John  Hyrcanus,  ruler from 134 to 104 B.C, expanded his domains to include the provinces of Idumaea and Samaria, parts of Galilee, and territories east of the Jordan River. He subsequently colonized these regions and forced their inhabitants to adopt Judaism. Alexander Jannaeus,  who became king from 103 to 76 BC , forced the Ituraeans  and  Arameans inhabitants in Galilee whose spoke Aramean (with Saffuriyya (Sepphoris)) to convert to Judaism.  

During this period, Saffuriyya (Sepphoris) was mentioned for the first time  by Flavius Josephe, when Ptolmey Lathyrus  had attacked it in 103 B.C, during his war against Alexander Jannaeus.