Caesarea was destroyed by the Sassanid king Shapur I after his victory over the Emperor Valerian I in AD 260. At the time it was recorded to have around 400,000 inhabitants. The city gradually recovered, and became home to several early Christian saints: saints Dorothea and Theophilus the martyrs, Gregory of Nazianzus, Gregory of Nyssa and Basil of Caesarea. In the 4th century, bishop Basil established an ecclesiastic centre on the plain, about one mile to the northeast, which gradually supplanted the old town.[7] It included a system of almshouses, an orphanage, old peoples' homes, and a leprosarium (leprosy hospital). The city's bishop, Thalassius, attended the [8] Second Council of Ephesus and was suspended from the Council of Chalcedon [9]

A Notitia Episcopatuum composed during the reign of Byzantine Emperor Heraclius in about 640 lists 5 suffragan dioceses of the metropolitan see of Caesarea. A 10th-century list gives it 15 suffragans.[10] In all the Notitiae Caesarea is given the second place among the metropolitan sees of the patriarchate of Constantinople, preceded only by Constantinople itself, and its archbishops were given the title of protothronos, meaning "of the first see" (after that of Constantinople). More than 50 first-millennium archbishops of the see are known by name, and the see itself continued to be a residential see of the Eastern Orthodox Church until 1923, when by order of the Treaty of Lausanne all members of that Church(Greeks)were deported from what is now Turkey.[11][12][13] Caesarea was also the seat of an Armenian diocese.[14] No longer a residential bishopric, Caesarea in Cappadocia is today listed by the Catholic Church as a titular see of the Armenian Catholic Church and the Melkite Catholic Church.[15]
Kayseri city walls in 2006
A portion of Basil's new city was surrounded with strong walls, and it was turned into a fortress by Justinian. Caesarea in the 9th century became a Byzantine administrative centre as the capital of the Byzantine Theme of Charsianon.