St. Paul's has stood as a Christian witness in the life of the Des Moines community for more than 150 years. The city was incorporated at Fort Des Moines on January 18, 1853; St. Paul's held its first services with ten communicants on October 15, 1854.
A building campaign was started in 1856, and in 1857, a brick and frame church was completed, for about $4,100, on a $500 lot on Seventh Street, between Locust and Walnut, now the site of the former Younkers Department Store.
In 1870, feeling the need to replace the property, the congregation bought two lots on the northeast corner of Ninth and what is now High Street. The new church was completed in 1885.
St. Paul's history is characterized by its commitment to ministry as a downtown church. Church members have repeatedly affirmed and reaffirmed their intent to remain at the present site, restoring the church repeatedly over the years. At the same time, it has provided substantial direction and financial support in the establishment of mission churches in the Des Moines area: St. Luke's in 1905, St. Andrew's in 1950, and St. Timothy's in 1960.
In 1996, St. Paul's became a cathedral and the liturgical center of the Diocese of Iowa.