In 1722, there were three churches in Biryuche: the Protection, Annunciation, and Trinity churches, located in Zasosna.

On October 1, 1779, a new wooden church was consecrated in honor of the Protection of the Holy Virgin. When Biryuche became a district town and the center of the diocese, the Protection church gained the status of a cathedral. Documents from the military college during the reign of Catherine II mention the holding of funerals in this cathedral, in particular, for Colonel Domián Yelistratov and Major General Vladimir Iovich Narykov, for whom the rite was performed by the vicar archbishop of Voronezh, Agafon. By the mid-19th century, the wooden cathedral had deteriorated and could not accommodate all the parishioners. In 1832, after the completion of the Assumption church, the Holy Synod blessed the collection of donations for the construction of a new stone cathedral. The funds allocated from the treasury were insufficient, so the clergy and parishioners collected additional donations. The bell tower was built later. By the Feast of the Protection in 1838, the cathedral was completed.

Many notable people noted the beauty and splendor of the cathedral's interior. Among them were composer Bortnyansky and writer Danilevsky. Artist Kramskoy used the cathedral's frescoes to create the image for his future painting "Christ in the Desert."

According to the memories of the locals, the Biryuche cathedral had four altars. It was decorated by the best icon painters of the city and province, including the Zhitnikov brothers, who had an icon painting workshop in Biryuche.

In 1862, a theology class of the Voronezh Bishop's School opened at the Protection Cathedral, and in 1902, the cathedral priests began teaching the Law of God in the parish school at the Assumption church. During these years, before and after serving at the Sviyazhsk-Kazan diocese, Bishop Dmitry (Sambikin) often visited here.

After the revolution, the cathedral was desecrated; in 1922, all valuables were confiscated, and the clergy were dispersed for refusing to join the "Renovationist" movement.

In 1961, the cathedral building was converted into a district House of Culture: the domes and bell tower were demolished, and the roof was raised. The outer walls remained, with a vestibule with a film projection room added on the eastern side and a boiler room on the western side. The basement was partially filled with debris. The church part of the building became an assembly hall with a balcony. The House of Culture operated in the building until 2004.

From September 2004 to August 2005, as part of the preparations for the anniversary of the city of Biryuche, the cathedral was renovated, and a three-tiered bell tower was built. The cathedral was consecrated on September 11, 2005.