The Parthian Empire's control over Mesopotamia, a key region in the ancient Near East, began in the mid-2nd century BCE with Mithridates I of Parthia's conquests. This period marked a significant shift in the political and cultural landscape of Mesopotamia, transitioning from Hellenistic to Parthian influence. Mithridates I, who reigned from 171-138 BCE, is credited with expanding Parthian territory into Mesopotamia. He captured Seleucia in 141 BCE, a pivotal moment that signaled the decline of Seleucid power and the rise of Parthian dominance in the region. This victory was more than a military success; it represented the shifting balance of power from the Greeks to the Parthians in the Near East.

Under Parthian rule, Mesopotamia became a crucial region for trade and cultural exchange. The Parthian Empire, known for its tolerance and cultural diversity, allowed various religions and cultures to flourish within its borders. Mesopotamia, with its rich history and strategic location, played a significant role in this cultural melting pot.

Mesopotamia under Parthian rule saw a fusion of Greek and Persian cultural elements, evident in art, architecture, and coinage. This cultural synthesis was a testament to the Parthian Empire's ability to integrate diverse influences while maintaining its identity.

In the early 2nd century CE, Emperor Trajan of Rome led an invasion into Parthia, successfully conquering Mesopotamia and converting it into a Roman imperial province. However, this Roman control was short-lived, as Trajan's successor, Hadrian, returned Mesopotamia to the Parthians soon after.

During this period, Christianity began to spread in Mesopotamia, having reached the region in the 1st century CE. Roman Syria, in particular, emerged as a focal point for Eastern Rite Christianity and the Syriac literary tradition, indicating a significant shift in the religious landscape of the area.

Meanwhile, the traditional Sumerian-Akkadian religious practices began to fade, marking the end of an era. The use of cuneiform, the ancient writing system, also saw its decline. Despite these cultural shifts, the Assyrian national god Ashur continued to be venerated in his home city, with temples dedicated to him as late as the 4th century CE.^[45] This suggests a continued reverence for some aspects of the region's ancient religious traditions amidst the rise of newer belief systems.