Hecatomnus was the son of Hyssaldomus, the local ruler of Mylasa, a town in Caria. In 392 or 391, the Persian king Artaxerxes II Mnemon appointed Hecatomnus as satrap of the part of the Achaemenid Empire, and ordered him to build an army. Joining his forces with those of Autophradates of Lydia, he was supposed to subdue the rebel leader Euagoras of Salamis, who was aiming at an independent Cyprus. If we are to believe Diodorus of Sicily, this was all the more remarkable, because Hecatomnus had - together with Athens and pharaoh Achoris - also supproted Euagoras' revolt.note The war against Euagoras was finished in 385/384, with Cyprus becoming Persian again.
Later, Artaxerxes II later awarded Hecatomnus the overlordship of the city of Miletus, the largest Greek settlement in Asia Minor. He seems to have been fascinated by Greek culture, and on one occasion sent his youngest son Pixodarus to Athens, but from a religious point of view he always remained a Carian. His coins show a Greek-style representation of the native Zeus Labraundos.
According to the Athenian orator Isocrates, Hecatomnus wanted to start a rebellion against the Achaemenid king, but never executed his plans. He died in 377/376 and was succeeded by his son Maussolus. His house was to rule Caria for another half century.