On May 29, 1494, the second well-known local fool for Christ, John, died in Ustyug, who was canonized at the Council on February 26, 1547. He was buried in the Cathedral Square between the Assumption and Prokopyev Cathedrals. A few years later, a local resident, Fyodor Tutygin, built a church over his grave in honor of the Origin of the Honorable and Life-Giving Cross, with an altar dedicated to John. Since 1683, this church became the cathedral temple and the third shrine of the cathedral complex. Like other churches, it was repeatedly burned and restored.

On February 8, 1656, by the order of the Metropolitan of Rostov, Jonah, and with the funds of merchant Nikifor Revyakin, a stone church was laid in place of the wooden church in honor of the Origin of the Honorable Cross, with an altar in honor of the Righteous John of Ustyug. The construction was completed in 1663. The temple had five domes and a bell tower on the southern side with six bells. In 1695, by the order of the Ustyug bishop Alexander, the bell tower was dismantled, and the materials were used for the construction of the archbishop's courtyard, as was the bell tower of the Prokopyev Cathedral.

In 1830, the John Cathedral underwent reconstruction: the dome was changed, and the heads were completely replaced. In 1859, a large refectory was added to the western side. On January 15, 1909, the vault collapsed, but there were no casualties, and the icons were unharmed. On May 13, 1912, an altar was laid in honor of the Great Martyr and Healer Panteleimon and the Holy Martyrs Faith, Hope, Love, and their mother Sophia. Until 1917, the tomb of the Righteous John of Ustyug was located in the John Cathedral.

Among the ancient icons in the church, one can highlight the image of the Life-Giving Trinity, the image of the Origin of the Honorable and Life-Giving Cross of the Lord, as well as the image of the Holy Righteous John. A large ancient image of the Holy Righteous John of Ustyug the Miracle Worker, with his life and miracles, stands out. On the front side of the image, on a silver plate, there was an inscription: "In the year 7110, this image for the home church with a cover and with a brush and with a veil was set up by Nikita Grigoryev, son of Stroganov." On the back side, it was noted: "In the year 7110, on the 14th day of June, this image was made in Veliky Ustyug at the miraculous tomb of the Holy Righteous John of Ustyug the Miracle Worker by Nikita Grigoryev, son of Stroganov." Blessed John, the Ustyug Miracle Worker.