In the early 19th century, the area where the Protection Cathedral was located was on the outskirts of the city. In 1805, a city cemetery was opened here, where a wooden church was built in honor of St. John the Baptist with an altar in the name of the Exaltation of the Holy Cross. Over time, the city blocks approached the cemetery, the number of parishioners increased, and the old church became cramped and dilapidated.

In 1853, merchants Shikhobalovs, Anton, Emelyan, and Matvey, along with residents of nearby quarters, appealed to the Samara Bishop Eusebius Orlinsky with a request to allow the construction of a new stone church to replace the wooden one. The project, developed by provincial architect A.I. Maisner, was sent to St. Petersburg but was not approved. In 1857, the project by architect E.I. Zhiber was accepted. At this time, the cemetery church received the status of a parish church, and the cemetery was closed.

Anton and Emelyan Shikhobalovs donated 34 thousand rubles for construction, which covered the costs of stone masonry and interior decoration. Construction work began in July 1857, and on September 14 of the same year, Bishop Theophil Nadezhdin solemnly laid the church's foundation. The construction committee included the Shikhobalov brothers, priests Ioann Slovoakhtov and Alexander Tsaregradsky, as well as parish trustees. Anton Shikhobalov became the treasurer of the committee and the first church elder.

The construction was carried out diligently and was completed in two years. For their diligence in erecting the church, the Shikhobalov brothers were awarded gold medals, and Parshensky received the Order of St. Stanislaus of the 3rd degree. A family crypt of the Shikhobalovs was arranged in the churchyard.

On July 17, 1861, the main altar was consecrated in honor of the Protection of the Holy Virgin, and on November 12 of the same year, the right altar in the name of St. Mitrophan. The first rector was Archpriest Alexander Tsaregradsky, and after his death, his brother Nikolai.

Although the church was planned as a three-altar church, for a long time, the left altar housed the sacristy and office. In 1906-1907, with funds from Pyotr Ivanovich Shikhobalov, an extension was made, where the office and sacristy were moved. In 1911, the left altar was consecrated in honor of St. Martyr Emilian.

The architecture of the Protection Church is executed in the style of Moscow temple architecture of the 17th century and accommodates up to 2000 people. The interior was richly decorated, the altars faced with artificial marble, and the walls covered with frescoes. The icon of the Not-Made-By-Hands Image of Jesus Christ and the cross with the relics of saints were particularly venerated.

For 60 years, the church received generous donations from the Shikhobalov merchants. Anton Shikhobalov replaced the bell, paid for the church's facing, built a house for the clergy, and opened a Sunday school. In 1890, at his expense, the Protection Square was arranged.

After the 1917 revolution, the church came under the control of the Renovationists, but in 1938 it reunited with the Moscow Patriarchate. During the war years, the cathedral participated in fundraising, and its choir was one of the best in Russia.

In 1977, a fire occurred in the cathedral, destroying much of the painting. The restoration of the church lasted almost four years. In 1991, the Shikhobalov crypt was opened, and the remains were reburied on the church's territory.

Today, the Protection Cathedral conducts regular services and spiritual-educational work. In the future, it may yield the status of a cathedral to a new cathedral, but it will remain an important part of the history of the Russian Orthodox Church and the Samara diocese.