He was born early in the seventh century in the East. His birthplace is unclear: the Great Horologion says that he was born in eastern Arabia (present-day Qatar); the Synaxarion that he was born in Kurdistan. While still young he entered the Lavra of St Matthew with his brother, but after a few years of monastic life, having advanced far in obedience and the practice of prayer, he withdrew into the desert. His reputation for holiness reached the city of Nineveh, where the people prevailed on the hierarchy to consecrate him as their bishop in 670. Reluctantly but obediently, St Isaac took up the duties of shepherd of his flock in Nineveh. After a few months, he was called on to settle a dispute between two of the faithful, but they rejected his counsel and said 'Leave your Gospel out of this matter!' The holy bishop said, 'If they are not prepared to obey Our Lord's commandments, what need have they of me?', and retired to live as a hermit in the mountains of Kurdistan. Later, he settled in the monastery of Raban Shapur, where he wrote his Ascetical Homilies and other jewel-like works on the spiritual life. There he reposed in peace.

The fame of St Isaac' Homilies spread, and about one hundred years after their writing they were translated from Syriac into Greek by two monks in Palestine. In this form they spread throughout the monastic world, becoming a treasured guide to those who seek the fullness of the life of prayer. The Synaxarion says, "The book of Saint Isaac is, with the Ladder of Saint John Climacus, the indispensible guide for every Orthdox soul to journey safely toward God. Hence, not many years ago, a holy spiritual father, Jerome of Egina (d. 1966), recommended begging, if necessary, in order to be able to purchase a copy." We are blessed to have a good translation of the Ascetical Homilies available in English.

Saint Isaac is a very unusual case of an Orthodox Saint who lived outside the canonical boundaries of the Church: he was a bishop of the "Nestorian" communion, now sometimes called the "Oriental Orthodox." The purity of his own Orthodox faith is so clearly evident in his writings that the Church has nonetheless recognized his sanctity.