Diodore was born into a noble family in the area of
Antioch. He received a classic philosophical education at the school of Athens, and very quickly after his education entered into the monastic life.
 During this period, Diodore's work focused on philosophical treatises and opposing Emperor Julian's attempts to restore paganism in the empire. When an Arian named Leontius was made bishop of Antioch, Diodore and his friend
Flavian (who later was himself appointed as bishop of Antioch) organized those who followed the Nicene orthodoxy outside the walls of the city for worship. Those services are seen as the beginning of
antiphonal singing in the church, a practice that became widespread among Christians.
During his time at the monastery in Antioch, Diodore came under the tutelage of
Meletius of Antioch. Meletius was elected bishop in 360 and ordained Diodore as a
priest. When the Antioch split into factions, Diodore, in turn, was a strong supporter of Meletius and of his move towards Nicene orthodoxy.