The first military campaigns of Esarhaddon were directed against nomadic tribes of southern Mesopotamia, the Dakkuri and Gambulu, who had been harassing the peasants. In 679 BC the Cimmerians, who had already killed his grandfather Sargon, reappeared in Cilicia and Tabal under their new ruler Teushpa. Esarhaddon defeated them near Hubushna, and defeated the rebellious inhabitants of Hilakku as well. The Cimmerians withdrew to the west, where they were to destroy the kingdom of Phrygia in 676, together with Scythian and Urartian help.
The Sidonian king Abdi-Milkutti, who had risen up against the Assyrian king, was defeated in 677 BC and beheaded. The town of Sidon was destroyed and rebuilt as Kar-Ashur-aha-iddina, the Harbor of Esarhaddon. The population was deported to Assyria. A share of the plunder went to the loyal king of rival Tyre. The partly conserved text of a treaty with Tyre mentions the kings of Judah, Edom, Moab, Gaza, Ashkelon, Ekron, Byblos, Arvad, Samsi-muruna, Ammon, Ashdod, ten kings from the coast of the sea, and ten kings from the middle of the sea (usually identified with Cyprus), as Assyrian allies.
In 676 BC Esarhaddon took the towns of Sissu and Kundu in the Taurus mountains. The Mannaeans, the Scythians under their king Ishpakaia, and the Guti of the Zagros proved to be a nuisance as well, as is attested by numerous oracle-texts. The Mannaeans, former vassals of the Assyrians, were no longer restricted to the area around Lake Urmia, but had spread into Zamua, where they interrupted the horse trade between Parsuash and Assyria and refused to pay further tribute. After the fall of Phrygia, a daughter of Esarhaddon was wedded to the Scythian prince Partatua of Sakasene in order to improve relations with the nomads. The Medes under [Khshathrita (Phraortes) had been the target of a campaign as well, the date of which is unclear (possibly before 676 BC). Later, Assyrian hosts reached the border of the "salt-desert" near the mountain Bikni, that is, near Teheran. A number of fortresses secured the Zagros: Bit-Parnakki, Bit-kari and Harhar (Kar-Sharrukin).
A certain Mugallu had taken possession of parts of Meliddu (Melitene), and associated himself with the king of Tabal. Meliddu was besieged in 675 BC, but without success. That same year, Humban-Haltash II of Elam began a campaign against Sippar, but was defeated by the Babylonians, and died soon afterwards. His brother and successor Urtaki restored peace with Assyria.
A preliminary campaign against Egypt begun by Esarhaddon the next year seems to have failed. Meanwhile, Esarhaddon was waging war in the land of Bazu, situated opposite of the island of Dilmun (Bahrain), probably Qatar, "where snakes and scorpions cover the ground like ants" - a dry land of salt deserts. In 673 BC, Esarhaddon waged war against Urartu under king Rusas II, that had strengthened again after the ravages of Sargon and the Cimmerians.
In 672 BC, crown prince Sin-iddina-apla died. He had been the oldest son and designated as king of Assyria, while the second son Shamash-shum-ukin was to become the ruler of Babylon. Now, the younger Assurbanipal became crown prince, but he was very unpopular with the court and the priesthood. Contracts were made with leading Assyrians, members of the royal family and foreign rulers, to assure their loyalty to the crown prince.
In 671 BC Esarhaddon went to war against Pharaoh Taharqa of Egypt. Part of his army stayed behind to deal with rebellions in Tyre, and perhaps Ashkelon. The remainder went south to Rapihu, then crossed the Sinai, a desert inhabited by dreadful and dangerous animals, and entered Egypt. In the summer he took Memphis, and Taharqa fled to Upper Egypt. Esarhaddon now called himself "king of Musur, Patros and Kush", and returned with rich booty from the cities of the delta. Almost as soon as the king left, Egypt rebelled against Assyrian rule.
Esarhaddon had to contend with court intrigues at Nineveh that led to the execution of several nobles, and sent his general, Sha-Nabu-shu, to restore order in the Nile Valley. In 669 BC, he went to Egypt in person, but suddenly died in autumn of the same year, in Harran. He was succeeded by Assurbanipal as king of Assyria and Shamash-shum-ukin as king of Babylonia.