The land on which the present cathedral sits was purchased for $11,000 on March 6, 1810, as a site for a school for young Catholic men to be conducted by the Jesuits. This school failed, and in 1813 the land was sold again to Dom Augustin LeStrange, abbot of a community of Trappists (from the original monastery of La Trappe) who came to America fleeing persecution by French authorities. In addition to a small monastic community, they also looked after some 33 orphans. With the downfall of Napoleon in 1814, the Trappists returned to France, abandoning the property. The orphanage was maintained by the Diocese of New York into the late 1800s. Some of the monks resettled to Canada and eventually founded St. Joseph's Abbey in Spencer.

The Diocese of New York, created in 1808, was made an archdiocese by Pope Pius IX on July 19, 1850. On October 6, 1850, Archbishop John Joseph Hughes announced his intention to erect a new cathedral to replace the Old St. Patrick's Cathedral in downtown Manhattan. The "Old Cathedral" had been destroyed by fire in 1866 but was rebuilt and rededicated by 1868.

The new cathedral was designed by James Renwick, Jr. in the Gothic Revival style. The cornerstone was laid on August 15, 1858, just south of the diocese's orphanage. At that time, midtown Manhattan was far north of the populous areas of New York City.

Work was begun in 1858 but was halted during the Civil War and resumed in 1865. The cathedral was completed in 1878 and dedicated on May 25, 1879, its huge proportions dominating the midtown of that time. The archbishop's house and rectory were added from 1882 to 1884, and an adjacent school (no longer in existence) opened in 1882. The Towers on the West Facade were added in 1888, and an addition on the east, including a Lady Chapel, designed by Charles T. Mathews, was begun in 1901. The stained glass windows in the Lady Chapel were designed and made in Chipping Campden, England by Paul Vincent Woodroffe between 1912 and 1930. The cathedral was renovated between 1927 and 1931, when the great organ was installed and the sanctuary enlarged.

The cathedral and associated buildings were declared a National Historic Landmark in 1976.