The politics and wealth of western Asia attracted the attention of Rome. In 64 BC the Roman general Pompey incorporated Syria into the Roman Empire and the following year Judea was conquered and pro-Roman rulers appointed. By this time the River Euphrates marked the natural border between Roman power and the Parthian Empire in the east. Within the border zone were thriving cities profiting from trade such as Palmyra in the Syrian desert and Dura on the Euphrates.

Renewed Roman consolidation and expansion took place under the emperor Trajan (reigned AD 98-117). Both the Arabian Nabataean kingdom, based at Petra, and Palmyra were incorporated into the Roman Empire. With Syria and Arabia now secure, Trajan marched into Parthian territory as far as the Persian Gulf, although he retreated soon afterwards to the Euphrates. Antioch became an imperial residence and emperors were proclaimed there. The eastern link made stronger when Septimius Severus (reigned 193-211) married a Syrian princess, while Elagabalus (reigned 218-222) actually originated from the wealthy Syrian city of Emesa. In 224 the dynamic Sasanians from southern Iran defeated the Parthians and began to reverse Roman power.