The city is one of 16 cities of that the name founded by Seleucid ruler Antiochus I in 3C BC.In Roman times Emperor Augustus established the city as a military center because the city was strategically located on an east-west road. In the year 6 BCE, Praetor Cornutus Aquila ordered the construction of the road known as Via Sebaste. It connected Antioch with Perge on the Mediterranean coast. About 46 BCE, St. Paul came to Antioch in the company of St. Barnabas. They arrived from the coast, using Via Sebaste. St. Paul's visit in the city was most likely encouraged by Sergius Paulus, the governor of Cyprus, born in Antioch.

In the book of Acts Paul’s first and the longest recorded sermon (13:16—41) was delivered at the synagogue in Psidian Antioch.In the book of Acts he visited the city again on his two later journeys while travelling to points farther West (16:6;  19:1).

In AD 92 a severe famine threatened the city because of an unusually cold winter.And transportation problems made difficult the import of corn from the coast.

The site has an impressive setting  at 4,055  ft in the foothills of Sultandagi range.The size of the city was about 115 acres in its heyday.