Sennacherib (Assyrian: Sin-ahhe-eriba; 704-681) was well prepared for his position as sovereign. With him Assyria acquired an exceptionally clever and gifted, though often extravagant, ruler. His father, interestingly enough, is not mentioned in any of his many inscriptions. He left the new city of Dur-Sharrukin at once and resided in Ashur for a few years, until in 701 he made Nineveh his capital.

Sennacherib had considerable difficulties with Babylonia. In 703 Marduk-apal-iddina again crowned himself king with the aid of Elam, proceeding at once to ally himself with other enemies of Assyria. After nine months he was forced to withdraw when Sennacherib defeated a coalition army consisting of Babylonians, Aramaeans, and Elamites. The new puppet king of Babylonia was Bel-ibni (702-700), who had been raised in Assyria.

In 702 Sennacherib launched a raid into western Iran. In 701 there followed his most famous campaign, against Syria and Palestine, with the purpose of gaining control over the main road from Syria to Egypt in preparation for later campaigns against Egypt itself. When Sennacherib's army approached, Sidon immediately expelled its ruler, Luli, who was hostile to Assyria. The other allies either surrendered or were defeated. An Egyptian army was defeated at Eltekeh in Judah. Sennacherib laid siege to Jerusalem, and the king of Judah, Hezekiah, was called upon to surrender, but he did not comply. An Assyrian officer tried to incite the people of Jerusalem against Hezekiah, but his efforts failed. In view of the difficulty of surrounding a mountain stronghold such as Jerusalem, and of the minor importance of this town for the main purpose of the campaign, Sennacherib cut short the attack and left Palestine with his army, which according to the Old Testament (2 Kings 19:35) had been decimated by an epidemic. The number of Assyrian dead is reported to have risen to 185,000. Nevertheless, Hezekiah is reported to have paid tribute to Sennacherib on at least one occasion.

Bel-ibni of Babylonia seceded from the union with Assyria in 700. Sennacherib moved quickly, defeating Bel-ibni and replacing him with Sennacherib's oldest son, Ashur-nadin-shumi. The next few years were relatively peaceful. Sennacherib used this time to prepare a decisive attack against Elam, which time and again had supported Babylonian rebellions. The overland route to Elam had been cut off and fortified by the Elamites. Sennacherib had ships built in Syria and at Nineveh. The ships from Syria were moved on rollers from the Euphrates to the Tigris. The fleet sailed downstream and was quite successful in the lagoons of the Persian Gulf and along the southern coastline of Elam. The Elamites launched a counteroffensive by land, occupying Babylonia and putting a man of their choice on the throne. Not until 693 were the Assyrians again able to fight their way through to the north. Finally, in 689, Sennacherib had his revenge. Babylon was conquered and completely destroyed, the temples plundered and leveled. The waters of the Arakhtu Canal were diverted over the ruins, and the inner city remained almost totally uninhabited for eight years. Even many Assyrians were indignant at this, believing that the Babylonian god Marduk must be grievously offended at the destruction of his temple and the carrying off of his image. Marduk was also an Assyrian deity, to whom many Assyrians turned in time of need. A political-theological propaganda campaign was launched to explain to the people that what had taken place was in accord with the wish of most of the gods. A story was written in which Marduk, because of a transgression, was captured and brought before a tribunal. Only a part of the commentary to this botched piece of literature is extant. Even the great poem of the creation of the world, the Enuma elish, was altered: the god Marduk was replaced by the god Ashur. Sennacherib's boundless energies brought no gain to his empire, however, and probably weakened it. The tenacity of this king can be seen in his building projects; for example, when Nineveh needed water for irrigation, Sennacherib had his engineers divert the waters of a tributary of the Great Zab River. The canal had to cross a valley at Jerwan. An aqueduct was constructed, consisting of about two million blocks of limestone, with five huge, pointed archways over the brook in the valley. The bed of the canal on the aqueduct was sealed with cement containing magnesium. Parts of this aqueduct are still standing today. Sennacherib wrote of these and other technological accomplishments in minute detail, with illustrations.

Sennacherib built a huge palace in Nineveh, adorned with reliefs, some of them depicting the transport of colossal bull statues by water and by land. Many of the rooms were decorated with pictorial narratives in bas-relief telling of war and of building activities. Considerable advances can be noted in artistic execution, particularly in the portrayal of landscapes and animals. Outstanding are the depictions of the battles in the lagoons, the life in the military camps, and the deportations.

In 681 BC there was a rebellion. Sennacherib was assassinated by one or two of his sons in the temple of the god Ninurta at Kalakh. This god, along with the god Marduk, had been badly treated by Sennacherib, and the event was widely regarded as punishment of divine origin.