Stratonikeia was founded at the beginning of the 3rd century BC by the Seleucid king Antiochos I and named after his wife Stratonike. Archaeological finds such as bronze grave goods, pottery and two chamber tombs near the town indicate that the town probably originated from a Carian predecessor settlement.

The town's territory also included neighbouring villages.  In addition to the towns of Tendeba, Astragon and Pedasa, mentioned by Titus Livius and Strabon, it also included Lagina with its sanctuary of Hecate and Panamara with a sanctuary of Zeus. The possession of these also supra-regionally important sanctuaries could also be used as a power factor in political-military conflicts. Since a tribute by Sulla (Roman dictator) around 88 B.C., the villages Themessos and Keramos also belonged to the catchment area, so that Stratonikeia extended as far as the south coast. The city was thus a member of the Chrysaorian League of the Carians via its suburbs, although its core area was not in its catchment area.

Around 240 BC the Seleucids left Stratonikeia to the rule of Rhodes. Later the city was conquered by the Macedonians. In 197 B.C. the Rhodians tried to reconquer Stratonikeia, but this failed. After the defeat of the Macedonians 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 surrender Stratonikeia again; the Romans declared it a free city. In 133 B.C. Stratonikeia briefly became the headquarters of the rebel Aristonikos, who finally had to relinquish the city. In the First Mithridian War the city was conquered, occupied and fined by Mithridates VI in 88 BC. After the reconquest by the Romans, Sulla honoured the inhabitants for their loyalty; in 81 the status as a free city was confirmed. In 40 BC the Parthians besieged the city in vain with their commander Quintus Labienus. Stratonikeia retained its autonomy even under Roman rule in the province of Asia. In late antiquity the city became a bishop's seat, which is the origin of the titular bishopric Stratonicea in Caria.

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