The first church on the site of the Spaso-Preobrazhensky Cathedral was laid shortly after the founding of Nizhny Novgorod. It was a church in honor of the Transfiguration of the Lord, built by Grand Duke Yuri Vsevolodovich of Vladimir between 1225 and 1227. When the Nizhny Novgorod principality became independent, Prince Konstantin Vasilyevich constructed a large cathedral on its site, also in honor of the Transfiguration of the Lord, consecrated in 1352. An ancient icon of the Savior Not Made by Hands, painted in Greece, was brought here from Suzdal. In 1377 and 1378, the church suffered greatly from Tatar raids, but the icon was evacuated in time. In the 1380s, Grand Duke Dmitry Konstantinovich of Nizhny Novgorod restored the cathedral. In the 17th century, Tsar Mikhail Fyodorovich and Patriarch Filaret allocated funds for the construction of a new cathedral in gratitude to the Nizhny Novgorod people for liberating Moscow, as the old one had fallen into disrepair. The works were overseen by architect Lavrenty Vozoulin. The new church, built in the style of the Moscow Assumption Cathedral, was completed in 1632 but consecrated only in 1652 during the reign of Tsar Alexei Mikhailovich. The old cathedral stood nearby for over 40 more years. In 1672, the tombs of the Nizhny Novgorod princes and the remains of Kuzma Minin were transferred to the new cathedral. It became a cathedral church. In 1816, services ceased due to dilapidation, and in 1829 it was dismantled. A year later, a new five-domed three-altar cathedral was laid, consecrated in the autumn of 1834. Artist Zheleznov painted its walls by 1837. The lower church of the cathedral housed the tombs of princes, archbishops, and Kuzma Minin. In the early 1850s, Archbishop Jacob Vecherkov blessed the creation of three altars with iconostases in the lower church, and it became a "burial church." The main altar was consecrated in honor of the Kazan Icon of the Mother of God on August 26, 1851, the right one in honor of St. Demetrius of Thessalonica on October 26, 1853, and the left one on February 26, 1852, in the name of the Holy Martyrs Cosmas and Damian. The altars were consecrated in honor of the saints whose names were borne by Prince Pozharsky and citizen Minin. Initially, the cathedral had one altar in honor of the Transfiguration of the Lord, later two chapels were added: the right one in honor of the Icon of the Mother of God of All Who Sorrow, in memory of the dismantled cathedral, and the left one in honor of Prince George, the founder of Nizhny Novgorod. In the 1870s, a chapel was built on the northern side of the cathedral over Kuzma Minin's grave, designed by architect L.V. Dal, consecrated on August 12, 1874. Five years after its completion, the cathedral was visited by Marquis de Custine, impressed by its grandeur and ancient appearance.

To the west of the cathedral stood the bell tower. After the fire of 1715, which destroyed the old bell tower, Metropolitan Silvester Volynsky initiated the construction of a new stone bell tower in the form of an octagonal pillar with a tented roof. In 1716, ancient clocks from the Clock Tower of the Kremlin were transferred to it, which struck the small bells, the number of which reached twelve. After the revolution, the cathedral was closed in August 1918. In 1924 and 1929, the bell tower was dismantled, and the church itself was blown up in 1929 for the construction of the House of Soviets. Before the explosion, part of the tombs was opened, and the remains were transferred to the Regional Museum. During the excavation of the foundation for the House of Soviets, the tomb of Minin was recalled, and his remains were transferred to the museum. In 1962, on the 350th anniversary of the events of 1612, Minin's remains were reburied in the Mikhailo-Arkhangelsky Cathedral.

Currently, the building of the Nizhny Novgorod administration stands on the site of the Spaso-Preobrazhensky Cathedral. In 2005, a cross was erected nearby in memory of the cathedral, and in 2012, a chapel was built in honor of the Savior Not Made by Hands. In 2008, a stone cross in honor of Saints Cyril and Methodius, previously located at the Mikhailo-Arkhangelsky Cathedral, was moved to the House of Soviets.

In 2020, the reconstruction of the cathedral's bell tower began at the historical site as part of the preparations for the 800th anniversary of Nizhny Novgorod in 2021. The project also included the construction of a pedestrian bridge over Ivanovsky descent.