Thracians populated the area densely by 1200 BC. Miletians founded the apoikia (trading colony) of Odessos towards the end of the 7th century BC (the earliest Greek archaeological material is dated 600-575 BC), or, according to Pseudo-Scymnus, in the time of Astyages (here, usually 572-570 BC is suggested), within an earlier Thracian settlement. The name Odessos, first attested by Strabo, was pre-Greek, perhaps of Carian origin. A member of the Pontic Pentapolis, Odessos was a mixed Greco-Thracian community—contact zone between the Ionians and the Thracians (Getae, Crobyzi, Terizi) of the hinterland. Excavations at nearby Thracian sites have shown uninterrupted occupation from the 7th to the 4th century and close commercial relations with the colony. The Greek alphabet has been applied to inscriptions in Thracian since at least the 5th century BCE; the Hellenistic city worshipped a Thracian great god whose cult survived well into the Roman period.

Odessos presumably was included in the assessment of the Delian league of 425 BC. In 339 BC, it was unsuccessfully besieged by Philip II (priests of the Getae persuaded him to conclude a treaty) but surrendered to Alexander the Great in 335 BC, and was later ruled by his diadochus Lysimachus, against whom it rebelled in 313 BC as part of a coalition with other Pontic cities and the Getae. The Roman city, Odessus, first included into the Praefectura orae maritimae and then in 15 AD annexed to the province of Moesia (later Moesia Inferior), covered 47 hectares in present-day central Varna and had prominent public baths, Thermae, erected in the late 2nd century AD, now the largest Roman remains in Bulgaria (the building was 100 m wide, 70 m long, and 25 m high) and fourth-largest known Roman baths in Europe. Major athletic games were held every five years, possibly attended by Gordian III in 238 AD.

Odessus was an early Christian centre, as testified by ruins of ten early basilicas,^[6] a monophysite monastery, and indications that one of the Seventy Disciples, Ampliatus, follower of Saint Andrew (who, according to the Bulgarian Orthodox Church legend, preached in the city in 56 AD), served as bishop there. In 6th-century imperial documents, it was refereed to as "holiest city," sacratissima civitas. In 442, a peace treaty between Theodosius II and Attila was done at Odessus. In 536, Justinian I made it the seat of the Quaestura exercitus ruled by a prefect of Scythia and including Moesia, Scythia, Caria, the Aegean Islands and Cyprus. The Jireček Line, or the approximate linguistic frontier between Latin and Greek linguistic influence, ran through the Balkans from Odessus to the Adriatic.