On the assassination of his father in 281 BC, the task of holding together the empire was a formidable one. A revolt in Syria broke out almost immediately. Antiochus was soon compelled to make peace with his father's murderer, Ptolemy Keraunos, apparently abandoning Macedonia and Thrace. In Asia Minor he was unable to reduce Bithynia or the Persian dynasties that ruled in Cappadocia.
At the end of 275 BC the question of Coele-Syria, which had been open between the houses of Seleucus and Ptolemy since the partition of 301 BC, led to hostilities (the First Syrian War). It had been continuously in Ptolemaic occupation, but the house of Seleucus maintained its claim.
War did not materially change the outlines of the two kingdoms, though frontier cities like Damascus and the coast districts of Asia Minor might change hands.
His eldest son Seleucus had ruled in the east as viceroy from 275 BC(?) till 268/267 BC; Antiochus put his son to death in the latter year on the charge of rebellion. Circa 262 BC Antiochus tried to break the growing power of Pergamum by force of arms, but suffered defeat near Sardis and died soon afterwards. He was succeeded in 261 BC by his second son Antiochus II Theos.