In 432, the Athenians besieged the town, but because they needed their soldiers at the more important siege of Potidaea, they came to terms with the Macedonian king Perdiccas II, a son of Alexander. Thucydides, who informs us about this siege, does not offer details, but the fact that a treaty was concluded suggests that the Athenians had some sort of legal claim that Perdiccas recognized. It is likely that a Greek faction in the town had once asked Athens for protection, but that the pro-Macedonian faction had got the upper hand. Similar factions, one stressing the Greek origin and the other stressing the need to cooperate with the native population, are known from other Greek colonies and may have existed in Pydna too.In 410/409, the town revolted against king Archelaus, the son of Perdiccas, who received help from the Athenian commander Theramenes when he besieged the city. Eventually, the Macedonian took Pydna without support from his ally. Diodorus of Sicily tells that he ordered the inhabitants to abandon their houses and rebuild their town at a distance of four kilometers from the coast. The ancient city and port were controlled by the Macedonians, but the Greek city itself retained its independence until it was captured by the Athenian commander Timotheus during the crisis of succession that briefly destabilized Macedonia in 360. Its new king, Philip II, however, finally captured Pydna in 357. The city was to belong to Macedonia until Late Antiquity. After the death of Philip's son Alexander the Great in 323, queen-mother Olympias took refuge in Pydna with Alexander's wife Roxane and his infant son, who was also called Alexander. Here, she was besieged by Cassander (316). When Olympias surrendered, she was immediately executed; her daughter-in-law and grandson were killed in secret.
Pydna was again the scene of an important event in the year 168, when the Roman commander Lucius Aemilius Paullus defeated the Macedonian king Perseus, which meant the end of the independence of the old kingdom. Pydna suffered severely when the Romans looted the town. The town, fortunately, recovered and was to belong the the province Macedonia.
In the Byzantine age, Pydna was the seat of a bishop. The town was now named Kitros.