At a young age, Macarius was forced to get married against his will. Thus, he pretended to be sick and ask for his parents' permission to go to the wilderness to relax. At his return, he found that his wife had died, and shortly after, his parents departed as well. Macarius subsequently distributed all his money among the poor and needy. Seeing his virtues, the people of his village brought him to the bishop of Ashmoun who ordained him priest.
A while later, a pregnant woman accused him of having defiled her. Macarius did not attempt to defend himself, and accepted the accusation in silence. However, when the woman's delivery drew near, her labor became exceedingly difficult. She did not manage to give birth until she confessed Macarius' innocence. A multitude of people then came asking for his forgiveness, but he fled to the Nitrian Desert to escape all mundane glory.
While at the desert, he visited Anthony the Great and learned from him the laws and rules of monasticism. When he returned to the Scetic Desert at the age of forty, he presided over its monastic community for the rest of his life. Ten years after going into the desert, he became a priest.
For a brief period of time, Macarius was banished to an island in the Nile by the Emperor Valens, along with Saint Macarius of Alexandria, during a dispute over the doctrine of the Nicene Creed. At their return on 13 Paremhat, they were met by a multitude of monks of the Nitrian Desert, numbered fifty thousand, among whom were Saint Pishoy and Saint John the Dwarf.
The Apophthegmata edited with the homilies may also be genuine, but the seven so-called Opuscula ascetica edited under his name by Petrus Possinus (Paris, 1683) are merely later compilations from the homilies, made by Simeon the Logothete, who is probably identical with Simeon Metaphrastes (d. 950). Macarius likewise seems to have been the author of several minor writings, including an Epistola ad filios Dei, and a number of other letters and prayers.
The teachings of Macarius are characterized by a strong Pneumatic emphasis that closely intertwines the salvific work of Jesus Christ (as the 'Spirit of Christ') with the supernatural workings of the Holy Spirit. This 'Pneumatic' thrust in the Spiritual Homilies is often termed 'mystical' and as such is a spiritual mode of thought which has endeared him to Christian mystics of all ages, although, on the other hand, in his anthropology and soteriology he frequently approximates the standpoint of St. Augustine. Certain passages of his homilies assert the entire depravity of man, while others postulate free will, even after the fall of Adam, and presuppose a tendency toward virtue, or, in semi-Pelagian fashion, ascribe to man the power to attain a degree of readiness to receive salvation.
The debate concerning the 'extraordinary giftings' of the Holy Spirit in the post-apostolic age is given textual support by the Macarian Homilies in favor of a post-apostolic attestation of 'miraculous' Pneumatic giftings to include healings, visions, exorcisms, etc. The Macarian Homilies have thus influenced Pietist groups ranging from the Spiritual Franciscans (West) to Eastern Orthodox monastic practice to John Wesley to modern charismatic Christianity.