The parish was founded in 1894 in New York, in a rented space at 323 2nd Ave. Over time, the need for a larger place for the faithful arose. In 1899, a plot was acquired on 97th Street between Fifth and Madison Avenues, and in 1901, construction of the church began. The church was built thanks to donations from local parishioners and Russians from Russia, including a personal contribution from Emperor Nicholas II. In 1902, a grand consecration took place, led by Bishop Tikhon (Bellavin) of the Aleutian and Alaska Diocese, who became patriarch in 1917.

In 1904, the church was granted cathedral status. In 1905, the American diocese of the Russian Orthodox Church was moved from San Francisco to New York, and the cathedral became the residence of the archbishop. After the October Revolution, in 1924, the church came under the control of the 'Renovationists,' a modernist sect of Orthodox Christians supported by the Soviet government. To secure financial stability, including covering legal expenses, they sold parish property. By 1945, the church had passed into the jurisdiction of the Moscow Patriarchate. However, disputes in American courts over the ownership of the church continued between the Moscow Patriarchate and the North American Metropolia, to which the church belonged before being seized by the Renovationists. The issue was finally resolved in 1970 when the Russian Orthodox Church of the Moscow Patriarchate granted autocephaly to the North American Metropolia, and by the 'tomos,' the patriarchate received full rights to St. Nicholas Cathedral.

In 1973, the church was recognized as a landmark of New York architecture. From 2000 to 2003, with the support of the Russian government, restoration and fresco renewal were carried out. Services continue in both Slavic and English, and there is a parish school and youth organization.