Replacing the Greeks and the Seleucids, Roman emperors inherited already thriving cities--Damascus, Tadmur (once called Palmyra), and Busra ash Sham in the fertile Hawran Plateau south of Damascus. Under the emperor Hadrian, Syria was prosperous and its cities, major trading centers; Hawran was a well-watered breadbasket. After making a survey of the country, the Romans established a tax system based on the potential harvest of farmlands; it remained the key to the land tax structure until 1945. They bequeathed Syria some of the grandest buildings in the world, as well as aqueducts, wells, and roads that were still in use in modern times.

Neither the Seleucids nor the Romans ruled the area without conflict. The Seleucids had to deal with powerful Arab peoples, the Nabataeans, who had established an empire at Petra (in present-day Jordan) and at Busra ash Sham. The Romans had to face the Palmyrenes, who had built Palmyra, a city even more magnificent than Damascus and the principal stop on the caravan route from Homs to the Euphrates.

By the time the Romans arrived, Greater Syrians had developed irrigation techniques, the alphabet, and astronomy. In A.D. 324 the Emperor Constantine moved his capital from Rome to Byzantium, renaming it Constantinople (modern Istanbul). From there the Byzantines ruled Greater Syria, dividing it into two provinces: Syria Prima, with Antioch as the capital and Aleppo the major city; and Syria Secunda, ruled frequently from Hamah. Syria Secunda was divided into two districts: Phoenicia Prima, with Tyre as the capital; and Phoenicia Secunda, ruled from Damascus. (Most of Phoenicia Prima is now Lebanon.) The ruling families of Syria during this period were the Ghassanids, Christian Arabs loyal to Byzantium, from whom many Syrians now trace descent.