The first information about the Nicholas Cathedral is found in the Mosalsk church tithe of 1628, where it is described as a small wooden church with two chapels: the Georgian Icon of the Mother of God and the apostles Peter and Paul. It was located within the city fortress wall on a hill later known as Pyatnitskaya.

In the regular plan of 1779, in addition to the existing churches: the wooden Nicholas and the stone Pyatnitsky and Trinity, the construction of new churches in the city was planned.

On May 9, 1806, thanks to the funding from one of the wealthiest residents of the city, retired major A. S. Khlyustin, the construction of a new church began in the main trading square. The project was developed by the serf architect of the Khlyustins, Yefim Yegorovich Latyshev.

After the death of A. S. Khlyustin in 1909, his sons continued the construction of the cathedral: staff captain Semyon Antonovich, court councilor Mikhail Antonovich, and actual state councilor Nikolai Antonovich. The construction was completed in 1818.

On September 29, 1818, Bishop Antony (Sokolov) of Kaluga and Borovsk consecrated the cathedral in honor of St. Nicholas the Wonderworker. The next day, on September 30, the chapels in honor of the Georgian Icon of the Mother of God and the apostles Peter and Paul were consecrated.

From the old wooden church, church utensils and icons were transferred to the new cathedral. The bells were also moved to the new bell tower. A fence with towers at the corners was built around the cathedral, three of which served as chapels, while the fourth was used as a watchman's hut.

The church was served by priest Ioann Filippovich Chuprov, and his son Alexander Ivanovich Chuprov, who was baptized here, initially followed in his father's footsteps but later, upon entering the Imperial Moscow University, became a well-known economist and public figure.

In the late 1920s and early 1930s, the church, like many others, was closed, the bells and cross were thrown down, and the iconostasis was looted. In 1930, the vicar bishop of the Kaluga diocese, Stefan (Vinogradov), whose see was in the Nicholas Cathedral, was arrested. He, priest Ioannikiy Vinogradov, and deacon Ioann Nikolsky were sentenced to five years in corrective labor camps, later replaced by five years of exile. In the late 1930s, the dome of the cathedral was demolished.

After its closure, the building was used as a House of Culture, where dances were held and films were shown. After the war, it housed a library and a cinema. In the 1950s, the church was dismantled for bricks, leaving only the bell tower, which was used as a water tower. At one point, a red glowing star was even installed on it.

In 1999, at the initiative of the Mosalsk district administration, the restoration of the church began according to the old project. The bell tower was the first to be restored, and on January 1, 2000, the sound of bells rang out over Mosalsk. On June 11, 2000, Archbishop Kliment of Kaluga and Borovsk consecrated the foundation of the resurrecting cathedral. The construction was completed by the end of 2000 thanks to funding from the oil company Yukos.

During the restoration, a crypt with the remains of Major A. S. Khlyustin was discovered, who, according to his will, was buried in the cathedral. A silver plaque with records about the construction of the church was also found. In July 2000, Khlyustin's remains were re-consecrated and reburied.