The rise of the Sassanians is better documented than subsequent history, but even so there are conflicting versions of the origin of Ardashir. The first capital of Ardashir in Fars most likely was at Firuzabad, then known as Gor, although later in the reign of Ardashir it received the name Ardashir-khwarreh 'the glory of A', probably in honour of his victories over the Parthians. The Sassanians respected and feared the mighty Roman Empire and continued to designate the later Byzantine state by the same name, although they knew that different peoples lived in the enemy state and served in its armies. The Romans too learned to respect the Sassanians more than they had the weaker Parthians. Perhaps the most significant changes in outlook, culture and society in the third and fourth centuries, both in the Roman and the Sassanian worlds, were the changes in religion which marked the end of the old 'pagan' religions and the flowering of 'universal' religions.

In 539 BC Cyrus peacefully took possession of Babylon, and the kingdom of Iranian peoples, taken over by the Achaemenian dynasty from the Medes, expanded to become the first real world-empire of ancient history. Under the Seleucids and the Parthians the site of the Mesopotamian capital moved a little to the north on the Tigris to Seleucia and Ctesiphon. When Alexander the Great at last halted his victorious march, the eastern frontier of the Achaemenian kingdom, he saw as the final goal of his desires the rebuilding of Babylon. Parthian art or Mesopotamian art of the Arsacid period worked with borrowed elements of Greek fashion, but these quickly lost their essential character. The drama of the foundation of a new world-religion, which shook both the Christian west and Zoroastrian Iran, was also enacted in Mesopotamia. It was the assimilation of ancient oriental culture into the Achaemenian empire and its Iranian successor states that first gave "Babylonism" the vast world-historical pers.

In the Seleucid period, Mesopotamia served as a base for the Seleucid kings' attempts to extend their political and commercial power into the Persian Gulf region and along the eastern coastlands of Arabia. The Parthians and then the Sasanians made Ctesiphon, on the eastern bank of the Tigris in central Mesopotamia, their capital and the centre from which Iranian power radiated over Aramaic, and then increasingly Arab, Iraq. The 6th century was a propitious time for Persian intervention in South Arabia. In the sphere of architecture, Persian influence on the buildings of the Lakhmids, such as the palace of Khawarnaq, must have been decisive, and Persian models must have dominated the architecture of early Islamic Iraq. Persian artistic influences also penetrated across the Syrian desert to the structures of the Umayyad caliphs on the fringes of modern Syria and Jordan, where there was a symbiosis with the local hellenistic and Byzantine artistic and architectural traditions.