The Neo-Babylonian Empire, also known as the Second Babylonian Empire^[37] or the Chaldean Empire,^[38] was the last Mesopotamian empire ruled by native monarchs.^[39] It began with Nabopolassar's coronation in 626 BCE and was firmly established after the fall of the Neo-Assyrian Empire in 612 BCE. However, it fell to the Achaemenid Persian Empire in 539 BCE, marking the end of the Chaldean dynasty less than a century after its inception.

This empire signified the first resurgence of Babylon, and southern Mesopotamia overall, as a dominant force in the ancient Near East since the collapse of the Old Babylonian Empire (under Hammurabi) nearly a thousand years prior. The Neo-Babylonian period experienced significant economic and population growth, and a cultural renaissance. Kings of this era undertook extensive building projects, reviving elements from 2,000 years of Sumero-Akkadian culture, especially in Babylon.

The Neo-Babylonian Empire is particularly remembered due to its depiction in the Bible, especially regarding Nebuchadnezzar II. The Bible focuses on Nebuchadnezzar's military actions against Judah and the siege of Jerusalem in 587 BCE, leading to the destruction of Solomon's Temple and the Babylonian captivity. Babylonian records, however, portray Nebuchadnezzar's reign as a golden age, elevating Babylonia to unprecedented heights.

The empire's downfall was partly due to religious policies of the last king, Nabonidus, who preferred the moon god Sîn over Marduk, Babylon's patron deity. This provided Cyrus the Great of Persia a pretext for invasion in 539 BCE, positioning himself as a restorer of Marduk's worship. Babylon retained its cultural identity for centuries, evident in references to Babylonian names and religion up to the 1st century BCE during the Parthian Empire. Despite several revolts, Babylon never regained its independence.