In 1812, Father Louis William DuBourg was appointed bishop of St. Louis. One of his first priorities was the construction of the town´s first cathedral.

In 1826, DuBourg resigned and was succeeded as bishop by his assistant, Joseph Rosati. As the brick cathedral had never been fully completed, Bishop Rosati reached a decision to build a new and larger church. It was completed in 1834 with ceremonies attended by prelates from throughout the diocese.

The facade and portico of the edifice have inscriptions in Latin, with the name of God in Hebrew upon its pediment. On the interior were paintings from France, some of which are still in place today.

A special distinction was granted to the Cathedral in 1841 by Pope Gregory XVI. This was an indulgence which is only granted elsewhere to pilgrims who visit the seven basilicas of Rome.

Eventually the need for a much grander Cathedral became apparent and, in 1914, the title passed to the great new structure on Lindell Boulevard. At that time, the Old Cathedral became known officially as the Church of St. Louis of France. The surroundings of the old church became increasingly dismal until it was in the midst of an area of decrepit riverfront warehouses. However, the noble old edifice was returned to a position of physical prominence by the razing of the warehouses for the new riverfront Jefferson National Expansion Memorial.

The Old Cathedral was restored to its original appearance beginning in 1959. In the process, a forgotten oval window above the altar was uncovered and later incorporated into the restored original interior design.