Little is known of his early life. He was born in the region near Moscow about the year 1482. Only his mother's monastic name is known from his dedication to her in the ''Great [[Menaion]] Reader''. His secular name is believed to have been Mikhail. <ref>Makarii, (Petr Ivanovich Veretennikov, Archimandrite) ''Zhizn' i trudy Makariia, Mitropolita Moskovskogo i vseia Rusi'' (Sergiev Posad: Ves' Sergiev Posad, 2002).</ref>
In the late fifteenth century, Macarius received his [[tonsure]] as a [[monk]] at the St. Paphnutius Monastery in Borovsk, where he served through the [[Holy Orders|holy orders]] as a [[reader]], [[subdeacon]], [[deacon]], and then [[priest]]. It was at the [[monastery]] that Macarius mastered the art of [[iconography]]. He is also known to have been a firm supporter of [[Joseph Volotsky]], the proponent of monastic land ownership (possessors/Josephites), and his [[disciple]]s.
In February 1523, Metr. Daniel of Moscow raised Macarius to the rank of [[archimandrite]] of Luzhetsk Monastery in Mozhaisk, west of Moscow. It was at Luzhetsk Monastery that Macarius became acquainted with Basil III, the Grand Prince of Moscow. He was one of a few clerics who supported Basil's divorce (confounded to a convent) from the barren Solomonia Saburova and blessed his second marriage with Elena Glinskaya, mother of [[Ivan IV of Russia|Ivan IV]].