Father Hugh Gallagher built Virginia City's first Catholic church shortly after his arrival in 1860, but a strong wind blew the humble building down within two years. Father Patrick Manogue built its successor, known as St. Mary in the Mountains Church, shortly after he arrived on the Comstock in 1862. Bishop Eugene O'Connell dedicated the simple structure on July 17, 1864, a block south of where the current structure stands.

Manogue's Catholic church remained in use until 1870, when the growing population necessitated the construction of a larger building. Irish immigrants arrived in Virginia City by the thousands until they and their children represented a third of the population. Together with various other Catholics, they provided both the need and the source of revenue for a larger building.

Manogue completed the construction of a larger brick structure on the corner of E and Taylor Streets, which Bishop O'Connell dedicated on November 20, 1870. The spire of the church measured 127 feet, six inches from the ground to the top of the cross. Its Gothic style interior was built of wood and plaster with carvings colored in white and gold. The twenty-one-foot-tall altar was imported from France and weighed 6,700 pounds. It was fronted with figures of the Twelve Apostles among carved pillars and scrolls. Local papers reported the church bell as being the largest in the region—it weighed 2,264 pounds and held a 100-pound clapper. The bell was rung for the first time on October 23, 1870 at six o'clock in the morning when the church formally opened for service.

Most of this structure was destroyed in the Great Fire of 1875. The St. Mary in the Mountains Church that stands today was rebuilt on the ruins of the former church, and dedicated by Bishop O'Connell on September 16, 1877. That church incorporated the lower walls of its predecessor, but the spire was raised twelve feet, six inches higher than the previous one. Other changes included structural reinforcements to prevent damage from earthquakes and high winds. A pipe was added to spray water over the roof in case of fire. The interior of the church was reconstructed with a choir loft and galleries built into the sides. A Gothic style wooden altar replaced the previous one of plaster or stone. Gas lighting illuminated ornate redwood rafters and a sky-blue ceiling, supported by robust wooden columns. The Daughters of Charity made needlepoint pictures for the walls which were also adorned with Old World paintings.

The end of the boom days of the Comstock took its toll on the church, and its maintenance was largely neglected from 1897 until the mid-twentieth century. Worse, a group of so-called "mad monks" took over management in 1957 and soon stripped the church of most of its choir loft and ornate interiors because they were "too worldly." Not only did this destroy art that was created in large part by master European craftsmen, it destabilized the structure, making it prone to earthquake devastation. Nevertheless, a devoted congregation remains, which is dedicated to the preservation of one of Nevada's most photographed historic buildings. In December of 2008, the members obtained a $500,000 Save America's Treasures grant from the National Parks Service to help stabilize and restore the building. Private donations and foundation grants were being sought to pay for the rest of the planned $1.9 million project. Work began in early 2009.