Little is known of Domnus' early life. He was a friend of Theodoret of Cyrrhus and the nephew of the Bishop of Antioch, John I, who was a supporter of [[Nestorius]] at the [[Third Ecumenical Council|Council of Ephesus]], but later reconciled with [[Cyril of Alexandria]]. Domnus was a disciple of the anchorite [[Euthymius the Great|Euthymius]] in Palestine.
In 429, Domnus was [[ordination|ordained]] a [[deacon]] by Juvenal of Jerusalem when he was at the [[Lavra]] of Euthymius. In 431, Domnus learned that his uncle, John I the Bishop of Antioch, had become entangled in the [[heresy]] of [[Nestorianism]] and sought leave from Euthymius so that he could aid him. Euthymius counseled Domnus to remain and advised him that going to Antioch would probably be not to his advantage. Also, he advised him that he would probably not be successful in restoring his uncle's dignity. Turning aside Euthymius' advise, Domnus left the [[lavra]] without saying farewell to Euthymius. <ref>Vita S. Euthymii, cc. 42, 56, 57</ref>
In Antioch, Domnus gained much popularity and was elected John I's successor in 442 upon John's death in 441. Soon Bp. Domnus was ranked among the chief bishops in the East. In 445, he convened a [[synod]] of the Syrian [[bishop]]s that confirmed the deposition of Athanasius of Perrha. In 447, Domnus [[consecration of a bishop|consecrated]] Irenaeus as bishop of Tyre. <ref> Theod. Ep. 110; Labbe, Concil. t. iii col. 1275</ref> However, [[Theodosius II]] directed that the appointment be annulled because Irenaeus was involved in a second marriage (digamus) and was sympathetic to Nestorianism.