Antiochus II succeeded his father in 261 BCE, and thus began a new war for Syria. He reached an agreement with the current Antigonid king in Macedon, Antigonus II Gonatas, who was also interested in pushing Ptolemy II out of the Aegean. With Macedon's support, Antiochus II launched an attack on Ptolemaic outposts in Asia.

Most of the information about the Second Syrian War has been lost. It is clear that Antigonus' fleet defeated Ptolemy's at the Battle of Cos in 261 BCE, diminishing Ptolemaic naval power. Ptolemy appears to have lost ground in Cilicia, Pamphylia, and Ionia, while Antiochus regained Miletus and Ephesus. Macedon's involvement in the war ceased when Antigonus became preoccupied by the rebellion of Corinth and Chalcis in 253 BCE, possibly instigated by Ptolemy, as well as an increase in enemy activity along Macedon's northern frontier.

The war was concluded around 253 BCE with the marriage of Antiochus to Ptolemy's daughter, Berenice Syra. Antiochus repudiated his previous wife, Laodice, and turned over substantial domain to her. He died in Ephesus in 246 BCE, poisoned by Laodice according to some sources. Ptolemy II died in the same year.