The death of Ptolemy IV in 204 BCE was followed by a bloody conflict over the regency as his heir, Ptolemy V, was just a child. The conflict began with the murder of the dead king's wife and sister Arsinoë by the ministers Agothocles and Sosibius. The fate of Sosibius is unclear, but Agothocles seems to have held the regency for some time until he was lynched by the volatile Alexandrian mob. The regency was passed from one adviser to another, and the kingdom was in a state of near anarchy.

Seeking to take advantage of this turmoil, Antiochus III staged a second invasion of Coele-Syria. He convinced Philip V of Macedon to join the war and conquer the Ptolemies' territories in Asia Minor – actions which led to the Second Macedonian War between Macedon and the Romans. Antiochus quickly swept through the region. After a brief setback at Gaza, he delivered a crushing blow to the Ptolemies at the Battle of Panium near the head of the River Jordan which earned him the important port of Sidon.

In 200 BCE, Roman emissaries came to Philip and Antiochus demanding that they refrain from invading Egypt. The Romans would suffer no disruption of the import of grain from Egypt, key to supporting the massive population in Italy. As neither monarch had planned to invade Egypt itself, they willingly complied to Rome's demands. Antiochus completed the subjugation of Coele-Syria in 198 BCE and went on to raid Ptolemy's remaining coastal strongholds in Caria and Cilicia.

Problems at home led Ptolemy to seek a quick and disadvantageous conclusion. The nativist movement, which began before the war with the Egyptian Revolt and expanded with the support of Egyptian priests, created turmoil and sedition throughout the kingdom. Economic troubles led the Ptolemaic government to increase taxation, which in turn fed the nationalist fire. In order to focus on the home front, Ptolemy signed a conciliatory treaty with Antiochus in 195 BCE, leaving the Seleucid king in possession of Coele-Syria and agreeing to marry Antiochus' daughter Cleopatra I.