Domnus was ordained deacon by the Patriarch Juvenal of Jerusalem in 429 and remained at the Monastery of St. Euthymius in Palestine for two years.
In 431, he left the monastery to aid his uncle, Patriarch John I of Antioch, as part of the Nestorian controversy.
[citation needed] In 441, upon the death of his uncle, Domnus was elected successor with support he had acquired in Antioch.
In 447, Domnus II consecrated Irenaeus to the see of Tyre (Theodoret, Epistle 110); but emperor Theodosius II, commanded that the appointment should be annulled on the grounds that Irenaeus was both a digamus and a supporter of Nestorianism - Iranaeus had formerly been a Roman count and friend of Nestorius at Council of Ephesus, having helped protect him.
He was the only bishop then deposed and banished who was not reinstated after the Council of Chalcedon – though this may have been by request so he could retire to his beloved monastery.