The site on which the current church stands was used as a place of worship under the patronage of Thomas the Apostle as early as the sixth century. In the ninth century, Bishop Adelochus established a magnificent church with adjoining school, however both burned down in 1007, and again in 1144. In 1196, construction began on the façade of a new, fortress-like building with an imposing steeple, built in the Roman style. Interrupted several times, the building work was completed in 1521, in the style of the late Gothic. Around 1450, the church commissioned a set of oil on panel paintings dedicated to the Passion of Jesus. Most of the surviving panels of this once scattered set are now kept in the Staatliche Kunsthalle in Karlsruhe, which is why the anonymous master who painted them earned the notname of ″Master of the Karlsruhe Passion″. It is assumed that he is identical with the painter Hans Hirtz, recorded in Strasbourg before 1460. The upper right angle of the Christ Carrying the Cross shows the St. Thomas Church as it still looks today.
In 1524, the church, which had been a pillar of local Catholic faith thanks notably to the efforts of the canon and poet Gottfried von Hagenau, converted to the Protestant faith (Martin Bucer served there as a Pastor ), a status which it maintained despite annexation of Alsace to the Catholic France. It still administers the primary and secondary schools École Saint-Thomas and Foyer Jean Sturm, as well as the Séminaire Protestant, a seminary located in the adjacent Baroque building.
The church played a crucial part in the liturgical revival as the place where, from 1888, Friedrich Spitta tested new forms of church service, and where the Akademische Kirchenchor (English: Academic Chorus) was brought into being. Julius Smend came to preach regularly from 1893, and between 1894 and 1899, the Gesangbuch für Elsaß-Lothringen (English: Hymn Book for Alsace-Lorraine) was developed there.
On May 7, 2006, the church was the place of the official celebration for the creation of the Union des églises protestantes d'Alsace et de Lorraine (Union of the Protestant Churches of Alsace and Lorraine), or UEPAL.