Because of the historical significance of the church, it was left intact while all neighboring buildings were demolished to make way for the Gateway Arch and related park.

The earliest Catholic records suggest that a tent was used by an itinerant priest in 1766, but by 1770 a small log house was built on the site.

[5] This building, consecrated by the Reverend Pierre Gibault, an itinerant priest, on June 24, 1770, was expanded in 1776 to include a log church.

[7] These buildings began to be replaced in 1818 with a brick structure, on the orders of the Bishop Louis William Valentine Dubourg.

[11] After the elevation of the Diocese of St. Louis to archdiocese status in 1847, the cathedral became home to an early chapter of the Society of Saint Vincent de Paul, a Catholic charity for the indigent.

Both Archbishop Peter Richard Kenrick and St. Louis Mayor Bryan Mullanphy were counted among the founders of the chapter, initially dedicated to assisting immigrants at a time of waves of immigration from Ireland and Germany, but later expanding to all St. Louis residents.

[14] The tradition of care for the poor and needy was carried on in the early 20th century after the appointment of the Reverend John Tannrath to head the church on September 5, 1915.

[15] Tannrath not only refurbished the rectory and church, but also reestablished a parish school for local immigrant children.

[18] In 2015, the Basilica underwent a restoration, including: The current parish serves the needs of local parishioners, described as "few in number but strong in loyalty", along with working people and tourists.

[4][19] Built in Greek Revival style, the church is noted for its marble altars, a painting of Saint Louis venerating the Crown of Thorns given by Louis XVIII, King of France and Navarre, and an accurate copy of the painting of the Crucifixion by Diego Velázquez installed in the church in the latter half of the twentieth century.

[21] Bishop Joseph Rosati, who ordered the construction of the church, is interred in a vault underneath the sanctuary.