St. Paul was founded in 1834. Before St. Paul was established, the city had only one Catholic parish, St. Patrick. As the population of the city grew in the 1820's, it soon became obvious that the city would need another church to accommodate the growing Catholic congregation. On August 27, 1827, a meeting of the Pittsburgh Catholics was called to address the issue. As a result of the meeting, a committee was formed to purchase a site for a new church. The committee chose a lot on the corner of Grant Street and Fifth Avenue. The cornerstone of the new church was laid on June 24, 1829. However, the congregation was not wealthy and fund raising was slow. As a result, the church was not ready for occupancy until 1834. Even at that time, the church was not completed as the tower was not finished (it never was finished). On May 4, 1834, St. Paul was dedicated.
The next milestone in the history of the church occurred in 1843, when Pittsburgh became a diocese and St. Paul became the diocesan Cathedral. In 1844, the city of Pittsburgh decided to grade off the hill upon which the Cathedral sat. The streets were lowered a second time in 1847. As a result, the church ended up sitting on a mound of dirt towering 30 feet over the surrounding streets. This caused an undermining of the foundation. On January 27, 1850, a parish meeting determined that the church would have to be torn down and the lot graded off to the level of the street. Fund raising for a new church began immediately. However, before the parish could act, a fire destroyed the church on May 6, 1851.
Work immediately began on the new church and the cornerstone was laid on June 15, 1851. In September of 1853, the basement was completed and used for services. On June 24, 1855, the Cathedral was consecrated. The Cathedral served the community for the remainder of the century. However, by the turn of the twentieth century, the expansion of the business district made it necessary to move the Cathedral. In a meeting held on April 9, 1901, the decision was made to sell the existing property and buy another lot of land at the corner of Fifth Avenue and Craig Street in Oakland. The last Mass was celebrated on May 10, 1903. The church was torn down and the site is now occupied by the Union Trust Building. A new parish, Epiphany, was founded for the remaining parishioners. While the new Cathedral was being built, Epiphany also served as a temporary Cathedral. The cornerstone for the new Cathedral was laid on September 6, 1903 and the completed building was dedicated on October 24, 1906. Between 2005 and 2007 the Cathedral was extensively renovated.
With the turn of the century, trends in the Diocese of Pittsburgh began to reveal a decline in Mass attendance and sacramental participation. At the same time, the number of priests available for parish ministry also began to decline.
To address these challenges, Bishop David Zubik announced on April 12, 2015 a new diocesan initiative, On Mission for The Church Alive!, a consultative strategic planning process designed to foster viable, sustainable and vibrant parishes. As part of this process, the Bishop, in consultation with the faithful, began to consider new models of parish life based on pastoral needs, financial and temporal resources and available clergy.
In 2018, following the period of consultation, parishes were grouped together and served by a single clergy team to eventually form one new parish.
During this transition period, St. Paul Cathedral Parish remained an independent parish while sharing clergy and staff and eventually publishing a joint bulletin with the other parishes. This ended on July 1, 2020 when St. Paul Cathedral Parish merged with the parishes of St. Regis, Oakland; St. Rosalia, Greenfield; and St. Stephen, Hazelwood to form the new St. Paul Cathedral Parish. As part of the merger the Cathedral remained open as part of the new parish.