In Hellenistic and Roman times, the city was an important stop for merchants headed to Europe on the ancient Silk Road.

An earlier town or city associated with the Old Assyrian trade network can be traced to 3000 BCE, in ruined Kültepe, 20 km (12 mi) north-east.

In the first century of Roman rule, the Caesarea belonged to the only four major cities in the region, together with Koloneia, Melitene and Tyana.

[5] The city served as a imperial Roman mint factory and produced zinc and lead from mines of Delikkaya and Aladağ.

In the 4th century, bishop Basil established an ecclesiastic centre in the suburbs, consisting of numerous charitable institutions (including a system of almshouses, an orphanage, old peoples' homes, and a leprosarium), monasteries and churches, that was later called Basileias.

[7] The hypothesis that the modern city of Kayseri, situated about two miles from the site of Caesarea Mazaca, developed around this complex is not confirmed by archaeology.

In the seventh century, the city became part of the Byzantine border region and became a target of the annual razzias the Arabs conducted into Anatolia.

[13] Kayseri Castle, built in antiquity, and expanded by the Seljuks and Ottomans, is still standing in good condition in the central square of the city.

[16] A Notitia Episcopatuum composed during the reign of Byzantine Emperor Heraclius in about 640 lists 5 suffragan dioceses of the metropolitan see of Caesarea.