Stratonicea was founded at the beginning of the 3rd century BC by the Seleukid King Antiochos I and named after his wife Stratonike. Archaeological finds such as bronze burial objects, pottery and two chamber graves near the town indicate that the town probably originated from a previous Carian settlement.

Adjoining villages also belonged to the territory of the town. In addition to the towns of Tendeba, Astragon and Pedasa, named by Titus Livius and Strabon, it also included the town of Lagina with its Hekate sanctuary and Panamara with a sanctuary of Zeus. The possession of these sanctuaries, which are also of supra-regional importance, could also be used as a power factor in political-military conflicts. Since a tribute by Sulla (Roman dictator) around 88 BC, the towns of Themessos and Keramos also belonged to the catchment area, so Stratonikeia extended as far as the south coast. The city was thus, although its core area was not in its catchment area, through its suburbs member of the Chrysaorian League of the Karer.

Around 240 BC, the Seleucids left Stratonicea to the rule of Rhodes. Later the city was conquered by the Macedons. In 197 B.C. the Rhodians tried to reconquer Stratonikeia, but this failed. After the defeat of the Macedons in the Battle of Kynoskephalai in 197 BC, the city fell to the Seleucid king Antiochos III, who in turn handed it over to the Rhodians.

In 167 B.C. the Rhodians had to give up Stratonicea again; the Romans declared it a free city. In 133 BC Stratonikeia became the headquarters of the rebellious Aristonikos, who eventually had to give up the city. During the First Mithridatic War, the city was conquered, occupied and fined by Mithridates VI in 88 BC. After being reconquered by the Romans, Sulla honoured the inhabitants for their loyalty; 81 the status as a free city was confirmed. 40 B.C. the Parthians besieged the city with their general Quintus Labienus in vain. Stratonicea retained its autonomy even under Roman rule in the province of Asia. In late antiquity, the town became a bishop's seat, which led to the titular bishopric of Stratonicea in Caria.

The largely sunken remains can now be found on the Milas-Milas–Muğla road near the spoil heaps of a huge lignite mine. There are larger ruins of a theatre, a bouleuterion, a gymnasium, a double gate with nymphaion, a city fortification and other remains. A sacred road once led to the nearby sanctuary of the Hecate in Lagina (11 kilometres away).

In the course of the centuries, Greeks and Turks had settled in the former city area. In the eighties of the last century most of the inhabitants of the village (Eskihisar) left and built with state support a few kilometres further, towards Milas, a new Eskihisar. Except for the mosque at the entrance to the city and the present excavation building, almost all houses have been abandoned.