He lived in asceticism in the wild hills outside Antioch. For forty-five years he had no tent or house of any kind, but wandered from place to place, living in caves or in clefts. In his old age, his disciples finally prevailed on him to build a small hut. Altogether he spent seventy years living in solitary ascesis.

Once a hunter met the recluse and asked him what he did in the mountains. The Saint answered 'Like you, I have come to the mountain to hunt. I am hunting for God, whom I long to see. I ardently desire to catch Him and will never tire of so excellent a chase!'

Once the people of Antioch rioted and tore down a pair of statues of the Emperor Theodosius and his wife. Two generals came from Constantinople, planning to inflict a bloody punishment on the people. Saint Macedonian, learning of this, came to the city and sought out the generals, asking them to take a message to the Emperor: that he, being human and subject to weakness like all men, should not be immoderately angry with other men; and that he should not, in return for the destruction of lifeless images, destroy those who are the very image of God.

During his lifetime Saint Macedonian was granted the gifts of spiritual insight and wonderworking, by which he worked many miracles of healing for the people of Antioch and its surroundings. He reposed in peace around 430, and was buried with honor in Antioch.