Early attempts by Parthian rulers to take Babylon were short-lived, but in 141 BC they established their kingship by celebrating the New Year festival. Chronicles and astronomical diaries continued to be written. An independent ruler of Maysan in the Sealand, Hyspaosines, captured the port on the Tigris, took control of Bahrain and Failaka to control Gulf trade, and briefly claimed kingship of Babylon. He wrote in Aramaic. The Parthians regained control and rebuilt the Greek theatre. The old buildings and city plan continued to be in use, although the Summer Palace had been reroofed with terracotta tiles. New kinds of text were written on clay in cuneiform, astronomical science developed; an archive shows that temples were still active, and much older literature was still prized. Greek knowledge of the Epic of Creation was still alive in Athens from the time of Alexander until the sixth century AD. The cult of Bēl had spread west to Palmyra, to the Aegean island of Kos, and north to Edessa. In AD 116 Trajan visited the Summer Palace on a pilgrimage to the place where Alexander had died.

Darius I overcame rebellions and seized the throne of Babylon, but cuneiform scholarship continued and developed; religious practices did not change, nor did the great buildings on the citadel. The zodiac scheme came into use. The Achaemenid king took Babylonian royal titles and promoted the worship of Marduk for local purposes. Xerxes broke the continuity. Following an uprising, a purge led to the ending of many archives. The province of Babylon was divided in two. Subsequent Achaemenid kings continued to treat Babylon with reverence. Alexander the Great defeated Darius III, entered Babylon, retained the Persian satrap, and moved treasure from Susa and Ecbatana to Babylon. He was recognized as a god. Lack of sons at his premature death precipitated a civil war from which Alexander’s commander Seleucus emerged to take the throne jointly with his son Antiochus. The derelict ziggurat was demolished, but temples and rituals, chronicles and astronomical diaries, continued as before. Aramaic was widely used, and fewer texts were inscribed in cuneiform. Interest in the fall of Assyria and of the Babylonian empire is apparent in Greek literature. Famous scholars include Berossus and named astronomers. Parthians invaded and eventually ended the dynasty.