Macarius was born in Upper Egypt (Southern Egypt) around AD 300. As a young man, he was a saltpeter smuggler and became familiar with the desert. He was known for his wisdom and was called "old young man" by his friends. At the behest of his parents, Macarius got married, but his wife would soon die, along with his parents. He then gave all his money to the poor and sought out an elder to instruct him. The elder he attached himself to guided him in the spiritual science of watchfulness, fasting, and prayer. He also instructed him in the art of weaving baskets.

Sometime later, a pregnant woman accused him of lying with her. Macarius did not try to defend himself and accepted the charge in silence. However, when the woman's delivery drew near, her labour became exceedingly difficult. She could not give birth until she revealed the true father. When she did, the town came asking for his forgiveness, but he had fled into the Nitrian Desert to escape glory.

While in the desert, he visited Anthony the Great and learned monasticism from him. After he left, around the age of 40, he returned to his former desert and governed a monastic community there for the rest of his life.

St. Macarius is venerated in all Christian denominations, and his spiritual homilies have always been held in high regard throughout the ages.