According to tradition, Antioch dates back to the 3rd century BCE, founded by the Seleucid Dynasty, one of the Hellenistic kingdoms. But the history of the city cannot be separated from the history of the Lakes Region and of Pisidia. Research done in the area has shown habitation since the Paleolithic age.

Excavations and surveys made by D.M. Robinson and the University of Michigan around Yalvaç in 1924 uncovered artifacts from surrounding mounds that date back to the 3rd millennium BC.

In Antioch itself, no finds have emerged from the Proto-Hittite, Hittite, Phrygian or Lydian civilisations, but we know from Hittite records that the region was named "Arzawa" and that independent communities flourished in the region. These people did not come under the yoke of the Hittites, but fought beside them against the Egyptians in the Battle of Kadesh.

Over the ages, people were able to live independently in the Pisidian region because of its strategic position. Even the Persians, who conquered Anatolia in the 6th century BC and attempted to rule the area by dividing it into satrapies, were unable to cope with constant uprisings and turmoil.

The approach of some researchers who would like to connect the cult of Men Askaenos with the cult of the Phrygian Mother Goddess Cybele is controversial. The worship of Cybele, traces of which can be seen in Antioch, is not a result of Phrygian influence: the idea of a Mother Goddess dates back to the Neolithic age as is shown by idols and figurines exhibited in Yalvaç Museum.

Because of its location, Antioch in Pisidia became part of the trade route between Cilicia and Ephesus and contained a mixed population including many Jews, who had established a synagogue there. It was a thoroughly Hellenized Greek-speaking city. Paul twice visited it with Barnabas on his first evangelistic journey about 47-48 C.E. and preached in the synagogue, finding much interest. However, becoming jealous of the crowds that were attending, certain Jews stirred up some of the leading men and women of the city and threw Paul and Barnabas outside.