Strangely, he married a woman named Berenice, who was the daughter of his half-uncle Magus, king of Cyrenaica, but his sister was also named Berenice. 

It is doubtful that any modern television soap opera could fictionally match the intrigue and complexities of the world during the time of the Ptolemies. Ptolemy III Euergetes' father had been at war with Antioch under its king, Antiochus II Theos (the so called Second Syrian War). However, in 253, the king of Egypt was hard enough pressed to make his peace with Antiochus II. A device frequently used by the Ptolemies to make peace was the dynastic alliance, and thus Ptolemy II had offered his daughter, Berenice Syra to Antiochus II, along with "a vast dowry", possibly the revenues of Coele-Syria. However, in order to make this match, Antiochus II was required to repudiate his prior wife, Laodice, with a settlement that included a considerable domain. 

Shortly after taking the throne, Ptolemy was called to the support of his sister in Syria. Antiochus II died about the same time as Ptolemy II, probably of illness, but some say that it was court intrigue and that his first wife, Laodice, had the kings poisoned. This left two, ambitious queen mothers, Laodice and Berenice Syra, in a competition on behalf of their potentially regnant sons. Ptolemy III at once left for Antioch, but before he could reach the city, his sister and her son, his young nephew, had already been slain. This lead to the Third Syrian (or Laodicean) War. Ptolemy III apparently sacked Antioch in revenge for his sister and her son's death and occupied the city for a brief period between 246 and 244 BC, then continued campaigning into Babylonia for the next five years, until 241 BC. We believe that he fought a naval battle off Andros during this period, and though the evidence is conflictive, he appears to have lost it. He did manage to hold on to Seleucia-in Pieria, the port of Antioch, but many of his other victorious claims seem to have been either ephemeral or exaggerated. Apparently, he also maintained control of Ephesus and Lebedos, which was now renamed Ptolemais, as well as cities in Trace and on the Hellespont. However, so important was Seleucia-in Pieria that Ptolemy III made fifteen hundred talents of silver, amounting to about ten percent of his annual income, from its capture. 

Ptolemy III had left his wife, the other Berenice, as head of state, with a panel of advisors in Egypt. Berenice, though was not simply the "other Berenice". She is known by Hellenistic historians as Berenice II, the daughter of King Magas of Cyrene. She was a battle-seasoned equestrienne who raced victorious chariot teams at Nemea, and whose dedicated lock of hair was immortalized as a constellation by Callimachus. (The Lock of Berenike, a poem, elaborates the conceit that a lock of hair, dedicated to Aphrodite by Berenice in thanks for her husband's safe return from the Third Syrian War, disappeared and was rediscovered among the constellations by the astronomer Conon). However, when trouble erupted back in Egypt, he rapidly returned to put down the dissidents.

Ptolemy III Euergetes continued his father's policy of supporting anti-Macedonia allies during much of his reign. He largely financed the Achaean League, which opposed Macedonia at that time, and which consisted of a group of cities united in a confederacy. The league had a common federal citizenship, but each city retained independent control of their internal affairs. However, when the League came into conflict with Sparta in about 228 BC, Ptolemy III calculated that Sparta would prove a more effective ally against Macedonia, and therefore switched his backing to them. 

Though Ptolemy III seems to have had his problems in Egypt, history considers him a prudent ruler, which is demonstrated by the famous Canopus Decree of March 4th, 238 BC. The Decree, made by the Egyptian priesthood, paid homage to the king and his wife as Theoi Euergetai, "Benefactor Gods", for their contributions and promotion of Egyptian cults, especially those involving sacred animals (particularly the Apis and Mnevis bulls), but also for maintaining peace by means of a strong national defense system and for good government in general. As an example of the latter, the decree singles out Ptolemy's importation, at his own expense, of grain for the population when an inadequate Nile flood threatened nationwide famine, "in return for which things the gods have granted stability to their royal rule, and will give them all other good things for ever hereafter".  The decree, like the Rosetta stone, was to be inscribed in hieroglyphic, demotic and Greek and consecrated in temples of the first, second and third rank. 

Ptolemy III is credited with having begun the building of the great temple dedicated to Horus at Edfu in the tenth year of his reign (about 237 BC), but the main structure was not finished until 231 BC, in the reign of his son. The temple was formally opened in 142 BC during the Reign of Ptolemy VIII, although the reliefs on the great pylon were not finished until the reign of Ptolemy XII. Of course, this was certainly not his only building project. Among others, he is also credited with several structures at Karnak, for example. 

The king is also credited for recovering, during one of his campaigns abroad (the Third Syrian War), some of the sacred statues that the Persians had carried off during their rule of Egypt.

Like his father, Ptolemy III's reign of 25 years saw Egypt prosper and expand. He continued the work of his father and grandfather in Alexandria, particularly at the Great Library. In fact, he ordered all books unloaded on the Alexandria docks to be seized, and copies made of them. The Library kept the originals (marked "from the ships"), while the owners were provided with the copies. He is also said to have borrowed from Athens the official copies of all three tragedians (Aeschylus, Sophocles, Euripides) in order to correct the texts in the Library. He had to put up a considerable deposit for this loan, yet once he had his hands on the originals, he decided to forfeit his deposit and keep them. 

Upon his death, he was probably buried in Alexandria in the royal cemetery, and was succeeded by his eldest son, Ptolemy IV Philopator in 222 BC. 

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