Antioch was a centre of learning, especially in rhetoric: according to Libanios, professor of rhetoric in Antioch from 354, Athens and Antioch 'held aloft the torch of rhetoric', Athens for Europe and Antioch for Asia. Diodore was a native of Antioch where he learnt his theology, though he had also studied rhetoric at Athens. John Chrysostom came to be ranked with St Basil the Great and St Gregory the Theologian as one of the universal teachers of the Church. The learned ninth-century patriarch of Constantinople, Photius, praised him for the clarity and purity of his style, his brilliant fluency. One of John's most interesting works is his treatise On Priesthood, written 390/1 and beginning with an account of his early years and a defence of his flight from ordination by Bishop Meletios of Antioch. Like John, Theodore was born in Antioch and studied there, having Libanios as his teacher of rhetoric, and Diodore as his ascetical and theological master.

Fourth-century Antioch was an outstanding centre of biblical scholarship and of ecclesiastical confusion. The leading figures of the Antiochene school of biblical scholarship in the fourth century were staunch upholders of the faith of Nicaea. Diodore was the leading figure of the school in the middle of the century and bishop of Tarsus from 378. Theodore of Mopsuestia draws a distinction between the office of the exegete and that of the preacher in the introduction to his Commentary on John. For Theodore, the primary author of all scripture was the Holy Spirit. His work of commentary on the Psalms and on the minor prophets led him to pay more attention than the majority of early writers to the precise nature of inspiration. His judgement on New Testament commentaries is based wholly on the suitability of the sense of the disputed reading. Theodore's commentaries on the Old Testament show him as a scholar capable of acute historical observation.