The decline of Assyrian power after 780 was notable; Syria and considerable lands in the north were lost. A military coup deposed King Ashur-nirari V and raised a general to the throne. Under the name of Tiglath-pileser III (745–727), he brought the empire to its greatest expanse. He reduced the size of the provinces in order to break the partial independence of the governors. He also invalidated the tax privileges of cities such as Ashur and Harran in order to distribute the tax load more evenly over the entire realm. Military equipment was improved substantially. In 746 he went to Babylonia to aid Nabu-naṣir (747–734) in his fight against Aramaean tribes. Tiglath-pileser defeated the Aramaeans and then made visits to the large cities of Babylonia. There he tried to secure the support of the priesthood by patronizing their building projects. Babylonia retained its independence.Tiglath-Pileser

His next undertaking was to check Urartu. His campaigns in Azerbaijan were designed to drive a wedge between Urartu and the Medes. In 743 he went to Syria, defeating there an army of Urartu. The Syrian city of Arpad, which had formed an alliance with Urartu, did not surrender so easily. It took Tiglath-pileser three years of siege to conquer Arpad, whereupon he massacred the inhabitants and destroyed the city. In 738 a new coalition formed against Assyria under the leadership of Sam’al (modern Zincirli) in northern Syria. It was defeated, and all the princes from Damascus to eastern Anatolia were forced to pay tribute. Another campaign in 735, this time directed against Urartu itself, was only partly successful. In 734 Tiglath-pileser invaded southern Syria and the Philistine territories in Palestine, going as far as the Egyptian border. Damascus and Israel tried to organize resistance against him, seeking to bring Judah into their alliance. Ahaz of Judah, however, asked Tiglath-pileser for help. In 733 Tiglath-pileser devastated Israel and forced it to surrender large territories. In 732 he advanced upon Damascus, first devastating the gardens outside the city and then conquering the capital and killing the king, whom he replaced with a governor. The queen of southern Arabia, Samsil, was now obliged to pay tribute, being permitted in return to use the harbour of the city of Gaza, which was in Assyrian hands.

The death of King Nabonassar of Babylonia caused a chaotic situation to develop there, and the Aramaean Ukin-zer crowned himself king. In 731 Tiglath-pileser fought and beat him and his allies, but he did not capture Ukin-zer until 729. This time he did not appoint a new king for Babylonia but assumed the crown himself under the name Pulu (Pul in the Old Testament). In his old age he abstained from further campaigning, devoting himself to the improvement of his capital, Kalakh. He rebuilt the palace of Shalmaneser III, filled it with treasures from his wars, and decorated the walls with bas-reliefs. The latter were almost all of warlike character, as if designed to intimidate the onlooker with their presentation of gruesome executions. These pictorial narratives on slabs, sometimes painted, have also been found in Syria, at the sites of several provincial capitals of ancient Assyria.

Tiglath-pileser was succeeded by his son Shalmaneser V (726–722), who continued the policy of his father. As king of Babylonia, he called himself Ululai. Almost nothing is known about his enterprises, since his successor destroyed all his inscriptions. The Old Testament relates that he marched against Hoshea of Israel in 724 after Hoshea had rebelled. He was probably assassinated during the long siege of Samaria. His successor maintained that the god Ashur had withdrawn his support of Shalmaneser V for acts of disrespect.