Originally, a wooden church stood on the site of the stone cathedral, consecrated on October 6, 1552, in honor of the Annunciation of the Blessed Virgin Mary. Three years later, the Kazan Diocese was established, and the abbot of the Selizharov Monastery, Guriy Rugotin, was appointed as the new archbishop. The small wooden church could not serve as the center of a diocese covering vast territories, including Siberia. Therefore, nine years later, in 1561, at the order of Tsar Ivan Vasilyevich, 80 stone masons arrived from Pskov, led by Postnik Yakovlev and Ivan Shiryay, nicknamed Barma, the builders of St. Basil's Cathedral. The church was built from Volga limestone, mined on the opposite bank of the Volga. On August 15, 1562, the church was consecrated by the first hierarch of Kazan, Guriy.

The new white-stone cross-domed cathedral originally measured 18 sazhen in length and 7 sazhen 2 arshins in width, which is almost half the size of the modern church that has expanded after several reconstructions. The walls were topped with keel-shaped zakomaras, and the vault rested on six round pillars, similar to the Assumption Cathedral in the Moscow Kremlin. Instead of traditional sails, the central dome was supported by trompes.

In the 16th century, the cathedral's domes had a helmet-like shape. At the end of the same century, side chapels were added to the church: the northern in honor of Saints Peter and Fevronia of Murom and the southern in honor of Princes Boris and Gleb, connected by a porch that encircled the central cubic volume of the cathedral.

In September 1918, Kazan was besieged by Red Army soldiers. Lenin ordered to drive out the White Czechs at any cost, and the city was not spared: the Bolsheviks fired cannons at the Kremlin, destroying all five domes of the cathedral. The external appearance was restored only during renovations in 1973 and 1984.

After the city was captured, the Bolsheviks declared the Kremlin a military garrison, closing the entrance for citizens and evicting all organizations. All seven Kremlin churches were closed. The diocesan administration was moved to the John the Baptist Monastery. The Kazan Cathedral of the Mother of God Monastery began to serve as the cathedral.

Believers were allowed to take only the reliquary with the relics of Saint Guriy and a few icons from the cathedral. The relics were transferred to the Church of Nicholas of Tulsky in the Kazan-Mother of God Women's Monastery, and later to the Peter and Paul Cathedral. They now rest in the Church of the Yaroslavl Miracle Workers at the Arsk Cemetery, and a portion of the relics is placed in the recreated reliquary in the Annunciation Cathedral.

A rich collection of icons, liturgical vessels, and other church relics was looted by the Bolsheviks. Only three icons from the iconostasis, some books in the KSU library and the RT museum, and a few items from the sacristy survived.

In 1922, a decree was issued to liquidate church property, and some icons from Kazan churches became the basis for the department of ancient Russian art in the Kazan Provincial Museum. From the sacristy of the Annunciation Cathedral, 85 items were taken to the museum.

In 1920, the authorities allowed Renovationists to serve in the cathedral, but in 1925 it was closed again and transferred to the museum department. In 1922, the bell tower was destroyed, and later the porch leading to the church was demolished. In 1929, the Kazgorod Council received permission to dismantle part of the cathedral buildings, but the cathedral itself miraculously survived.

Soon, the church housed the State Archive of the TASSR, and a vegetable storage was arranged in the basement church. In 1977 and 1984, the external appearance of the cathedral was restored, and the domes and drums were rebuilt. In 1987, the central dome was gilded. After the reconstructions, the central volume of the building with three apses and six round pillars remained, as well as the foundations of two side chapels and fragments of frescoes.

The last restoration of the cathedral was carried out in 1995 and 2005. In 1995, the church was handed over to the State Historical and Architectural Museum-Reserve "Kazan Kremlin." In 1997, the State Archive of the TASSR was moved to another building.

To restore the interior of the cathedral, a Financial Support Fund was created, headed by Y. V. Pavlov. Icon painting and painting works were carried out by the interregional scientific restoration art management since 2000. A team of Moscow icon painters led by S. R. Bragin participated in the restoration of icons. The restoration was completed in 2005 for the 450th anniversary of the Kazan Diocese.

On July 19, 2005, the cathedral was consecrated again by Archbishop Anastasius of Kazan. The first liturgy in the revived cathedral was served by Patriarch Alexy II on July 21, 2005. The cathedral is active, and the first rector of the revived church was Hieromonk Mephodiy, who later became the rector of the Kazan Kizich Monastery.