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.
In 448, Bp. Domnus defended Ibas, the bishop of Edessa, against charges of preaching Nestorianism and, in a synod he convened at Antioch, won a decision in Ibas' favor. The synod went on to depose his accusers. However, Flavian, Bishop of Constantinople, intervened and revoked the sentence set by the synod. Flavian's action was then set aside after the original sentence was confirmed by a commission of three bishops that was formed by emperor Theodosius and Domnus to settled the issue.
In a letter to emperor Theodosius, Domnus was among the earliest of those who questioned the orthodoxy of the [[Eutyches]]. Eutyches, in opposing Nestorianism, asserted the other extreme, that his human nature and divine nature were combined into the [[Monophysitism|single nature]] of [[Christ]].