Descended from a family of Armenian patriarchs, Isaac was educated in the Hellenistic culture of Asia Minor and at Constantinople. After the death of his wife, he became a monk and c. 388, with royal support, was named catholicos of Armenia. He furthered Armenian monasticism and converted his residence into a monastery, integrating his patriarchal administration with the ascetical life of the monks. A reformer, Isaac tightened clerical discipline and enforced celibacy on Armenian bishops. He also established schools and churches and gained Constantinople's recognition of Armenian patriarchal rights, thus creating a distinctive and autonomous Armenian form of Christianity free from direct Greek Orthodox control. With the help of his auxiliary bishop, the monk Mesrop Mashtots, later a saint, Isaac began c. 391 the development of a Greek-inspired Armenian alphabet and literature. The two then directed a group of scholars in translating the Greek and Syriac versions of the Bible into Armenian, completing it c. 435. This linguistic achievement and the formation of an Armenian liturgy and ritual preserved Armenian unity during its partition under Greek and Persian rule.
Although he won toleration for the Armenian Church by the Persian overlords, Isaac was forced to resign his office c. 428 because of intrigues among the Armenian princes. He resumed the church leadership in 432 in response to popular clamour. A semi-legendary 8th-century history of Armenia Major credits Isaac with writing liturgical texts and music, biblical commentaries on the Old Testament, and a series of letters to the Byzantine emperor, to Proclus, patriarch of Constantinople, and to other Eastern prelates on the Christological controversy. At the national Armenian synod of Ashtishat (435), Isaac promoted the Orthodox doctrine of Christ's personal divinity and denounced the emphasis on his humanity as expressed by Theodore of Mopsuestia. Isaac's letters have been published in the French translation (1841) of the 8th-century history of Armenia Major. Frederick C. Conybeare produced an English version (1898) of partially authentic church legislation attributed to Isaac.