He named it after his wife Thessalonike, a half-sister of Alexander the Great and princess of Macedonia as daughter of Philip II. Under the kingdom of Macedonia the city retained its own autonomy and parliament and evolved to become the most important city in Macedonia.

Twenty years after the fall of the Kingdom of Macedonia in 168 BC, in 148 BC, Thessalonica was made the capital of the Roman province of Macedonia. Thessalonica became a free city of the Roman Republic under Mark Antony in 41 BC. It grew to be an important trade hub located on the Via Egnatia, the road connecting Dyrrhachium with Byzantium, which facilitated trade between Thessaloniki and great centers of commerce such as Rome and Byzantium.

Thessaloniki also lays at the southern end of the main north–south route through the Balkans along the valleys of the Morava and Axios river valleys, thereby linking the Balkans with the rest of Greece.

In 306 AD, Thessaloniki acquired a patron saint, St. Demetrius, a Christian whom Galerius is said to have put to death. Most scholars agree with Hippolyte Delehaye’s theory that Demetrius was not a Thessaloniki native, but his veneration was transferred to Thessaloniki when it replaced Sirmium as the main military base in the Balkans. A basilical church dedicated to St. Demetrius, Hagios Demetrios, was first built in the fifth century AD and is now a UNESCO World Heritage Site.