The Cathedral of the Assumption of the Most Pure Mother of God has a long and complex history. The first church on this site was likely built in the late 12th or early 13th century, although exact data is lacking. The Assumption Cathedral in Ustyug is first mentioned in chronicles in 1290, when Bishop Tarasiy consecrated a wooden building, bringing with him the bell "Tyurik" and the icon "Mother of God Odigitria." However, according to Peter Yurinsky, this occurred in 1282. The cathedral existed for about a century and was destroyed by fire in 1396.

A new building of the cathedral was constructed in 1397, but by 1398 it was looted and burned by the Novgorodians, who took the icon "Mother of God Odigitria." In 1399, by order of the Novgorod Bishop John, the construction of a new cathedral began, which stood until the fire of 1490. In 1491, at the request of local priests, Ivan III instructed Archbishop Tikhon to assist in the construction of a new church. In 1492, a new cathedral was laid, consecrated in 1493, but it too burned down in 1496. In 1502, the sixth building was constructed, which was destroyed by lightning in 1552.

From 1554 to 1558, the first stone church was erected, becoming the first stone cathedral in the Russian North. In 1619, reconstruction of the cathedral began, and in 1622 a new stone church was consecrated, which burned down in 1631. The construction of a new building continued from 1639 to 1663, and in 1658 it was consecrated. In 1663, the construction was completed by 28 stone masons from Yaroslavl. The new cathedral retained the monumental forms and centered composition characteristic of churches of this type.

From 1929 to 1976, the building was used as a warehouse. In 1986, four domes of the cathedral were gilded in Veliky Ustyug, and in 1988, restoration of the bell tower continued. In 1997, a new bell, gifted by Moscow entrepreneur Andrey Kondin, was raised to the bell tower. In 2008, bells for the cathedral's belfry were consecrated. Today, the bell tower of the Assumption Cathedral houses 10 bells.