After the Elamite occupation of Babylonia, the region saw significant political shifts, starting with Marduk-kabit-ahheshu founding the Dynasty IV of Babylon around 1155 BCE. This dynasty, originating from Isin, was notable for being the first native Akkadian-speaking South Mesopotamian dynasty to rule Babylonia. Marduk-kabit-ahheshu, only the second native Mesopotamian after the Assyrian king Tukulti-Ninurta I to rule Babylon, successfully expelled the Elamites and prevented a Kassite revival. His reign also saw conflict with Assyria, capturing Ekallatum before being defeated by Ashur-Dan I.

Itti-Marduk-balatu, succeeding his father in 1138 BCE, fended off Elamite attacks during his 8-year reign. His attempts to assault Assyria, however, ended in failure against the still reigning Ashur-Dan I. Ninurta-nadin-shumi, ascending the throne in 1127 BCE, also embarked on military campaigns against Assyria. His ambitious assault on the Assyrian city of Arbela ended in defeat by Ashur-resh-ishi I, who then imposed a treaty favorable to Assyria.

Nebuchadnezzar I (1124–1103 BCE), the most renowned ruler of this dynasty, achieved significant victories against Elam, reclaiming territories and the sacred statue of Marduk. Despite his success against Elam, he faced multiple defeats by Ashur-resh-ishi I in attempts to expand into territories formerly controlled by the Hittites. Nebuchadnezzar I's later years were focused on construction and fortifying Babylon's borders.

Nebuchadnezzar I was followed by Enlil-nadin-apli (1103–1100 BCE) and Marduk-nadin-ahhe (1098–1081 BCE), both of whom engaged in conflicts with Assyria. Marduk-nadin-ahhe's initial successes were overshadowed by crushing defeats by Tiglath-Pileser I, leading to substantial territorial losses and famine in Babylon.

Marduk-shapik-zeri (circa 1072 BCE) managed to sign a peace treaty with Assyria, but his successor, Kadašman-Buriaš, faced Assyrian hostility, resulting in Assyrian domination until around 1050 BCE. Subsequent Babylonian rulers like Marduk-ahhe-eriba and Marduk-zer-X were essentially vassals of Assyria.

The decline of the Middle Assyrian Empire around 1050 BCE, due to internal strife and external conflicts, allowed Babylonia some respite from Assyrian control. However, this period also saw the incursion of West Semitic nomadic peoples, particularly Arameans and Suteans, who settled in large parts of Babylonian territory, indicating the region's political and military vulnerabilities.