The Persian Achemenide kings struck up alliances with exiled aristocrats in order to oust the regional authorities loyal to their Babylonian rulers. This strategy was common throughout the vast Persian Empire from Egypt to present-day Pakistan. The Persian desire to take political, economic and spiritual power did not pass without arousing much resistance in the region; the most striking example was the conflict between the Judaeans and the Samaritans. During the two centuries of Persian domination, the region was divided into small provinces amongst which the most prosperous were undoubtedly the maritime cities, open to Mediterranean trade, particularly with Greece. At this time, the Phoenician suzerains (Tyre and Sidon) controlled the entire Mediterranean Levantine coast, with the exception of Gaza — the most important urban centre in the region, whose longstanding links with Greece were a prelude to its later hellenisation.

Rome conquered Palestine after it had first become involved in internal political struggles there during the Hasmonean dynasty. Pompey reduced Judaea to the state of a client state. From 37 to 4 BCE, the Roman Empire supported a man, loyal to Rome and whom they trusted, who ruled the province under the title of king (having been crowned in Rome in 40 CE by the Senate): Herod the Great, the son of an Arab princess and an Edomite. Herod kept Judaism as the official religion of the royal court, while also allowing the worship of Graeco- Roman gods and the imperial cult. He was a great patron of Graeco-Roman culture and was especially famed for his construction of palaces, temples and cities. On his death, his kingdom was absorbed by the Roman province of Syria, and Caesarea became the capital of the Roman governor.

Herod had spent state money lavishly; he also confiscated and divided up the land for his veteran soldiers and the Roman generals, causing a general impoverishment of the peasant masses. Popular revolts, tinged with messianic overtones, increased during the first century CE. In 132 CE, Hadrian announced the restoration of Jerusalem as a Roman colony, renamed Aelia Capitolina, dedicated to Jupiter Capitolina, and his prohibition of circumcision of infants then detonated a new revolt in the province of Palaestina Prima. The measure banning circumcision was not applied, but Jews were banned from entering Jerusalem, now named Aelia Capitolina, except for one day each year when they were permitted to wail at the ruins of the temple.

Palestine became the scene of frequent religious confrontations between pagans, Samaritans, Jews and the emerging Christian sects. From the end of the first century CE, Pharisee rabbis excluded Nazarenes, (the disciples of Jesus), from the synagogues. Still an obscure period, nevertheless it was a decisive time for the development of Christianity, which was seeking its identity and spreading with varying success. Critics of Christian currents note that conflicts between different groups of converts (whose interpretations were influenced by Judaism or paganism) was characteristic of this period of the formation of Christianity.