The monastery was founded in 1529, although there are reports that it occurred in 1505, by the venerable Gennady at the site of his cell, where he lived with his teacher, the venerable Cornelius of Komel. The central element of the monastery was the majestic five-domed Transfiguration Cathedral, built in 1647. In 1961, there was an attempt to blow it up, after which it remained in a ruined state until the 21st century, but it has now been largely restored. In the 1960s, the apple orchard was destroyed and the well of the venerable Gennady was filled in, which has now been restored, and a wooden church was built over it. Attempts to destroy the monastery buildings continued until the 1980s, and in 1988, the altar of the cathedral was demolished by tractors.

In 1644, the relics of the venerable Gennady were found in the monastery, which were initially kept openly, and then buried in the Transfiguration Cathedral. In the early 1920s, the monastery was closed, and the icons, utensils, and the relics of the venerable Gennady were taken to Yaroslavl.

By the beginning of the 20th century, there were three churches in the monastery: the Church of the Transfiguration of the Lord, the cathedral with five altars in the name of the Transfiguration of the Lord, Sergius of Radonezh, the venerable Gennady, the Annunciation of the Most Holy Theotokos, and the venerable Cornelius of Komel. According to other sources, there were two churches: the winter Transfiguration Church, built in 1647, and the summer church in the name of Alexius, the Man of God, from 1751. The monastery owned two chapels, one of which was within its walls, and the other on the bank of the Kostroma River in the village of Beloglazovo in the Lyubim district. The monastery also owned two houses in Yaroslavl and one in Lyubim.

A school operated at the monastery, and an annual procession was held on August 19. The monastery owned 65 desyatinas and 1757 square fathoms of land. There was a stone two-story building, a wooden abbot's house, and three wings with cells. In 1908, the monastery received 711 rubles and 42 kopecks in state funding and had a capital in securities amounting to 80,778 rubles. The monastery was classified as a third-class monastery, meaning it was funded from the treasury.

In 1996, the community of the Spaso-Gennady Monastery was established, and in 1997, the Committee for the Protection of Historical and Cultural Monuments of the Yaroslavl Region transferred the monastery complex to it. Restoration began.