A decade into his rule, Ptolemy II faced Antiochus I, the Seleucid king who was trying to expand his empire's holdings in Syria and Anatolia. Ptolemy proved to be a forceful ruler and skilled general. In addition, his recent marriage to his court-wise sister Arsinoe II of Egypt had stabilized the volatile Egyptian court, allowing Ptolemy to successfully carry out the campaign.

The First Syrian War was a major victory for the Ptolemies. Antiochus took the Ptolemaic controlled areas in coastal Syria and southern Anatolia in his initial rush. Ptolemy reconquered these territories by 271 BCE, extending Ptolemaic rule as far as Caria and into most of Cilicia. With Ptolemy's eye focused eastward, his half-brother Magas declared his province of Cyrenaica to be independent. It would remain independent until 250 BCE, when it was reabsorbed into the Ptolemaic Kingdom: but not before having triggered a sequence of Ptolemaic and Seleucid court intrigues, war and ultimately leading to the marriage of Theos and Berenice.