St Peter was also associated with Antioch, having been there at the time of St Paul and Barnabas. He is regarded as the founder of the church of Antioch and its first bishop. A grotto at the foot of the hills a bit east of the city is known as St. Peter's Grotto where early Christians met in secret, also designated by the papacy in 1963 as the world's first cathedral.

Ignatius was the third bishop of Antioch whose seven letters, among them one to Polycarp, the bishop of Smyrna, are among the earliest pieces of Christian literature. Tradition and some scholars hold that Saints Matthew and Luke lived and wrote their gospels in Antioch.

St. John Chrysostom, Patriarch of Constantinople (349-404 AD) was born in Antioch and got his early training here.He was the prize student of Libanios, the renowned 4 th century teacher. John became the greatest of all Christian preachers.

At the Council of Nicaea, in 325, Antioch was ranked with Rome and Alexandria as an episcopal see of exceptional authority in the church. At the council of Costantinople in 381, the imperial city of Constantinople itself was added to this list and during the councils of the fifth century Jerusalem, too, would gain its place. Thus the sees of Rome, Constantinople, Alexandria, Antioch and Jerusalem gained their ranks of honor as the pentarchy of the Great Church.