There are only a few historical facts known about the origin of the city. No traces of the presence of Hittites or Persians have been found. The Phrygians built a temple, probably in the first half of the 7th century BC. This temple, originally used by the citizens of the nearby town of Laodicea, would later form the centre of Hierapolis.

Hierapolis was founded as a thermal spa early in the 2nd century BC within the sphere of the Seleucid Empire. Antiochus the Great sent 2,000 Jewish families to Lydia and Phrygia from Babylon and Mesopotamia, later joined by more from Judea. The Jewish congregation grew in Hierapolis and has been estimated as high as 50,000 in 62 BC.