The current church is located on the site of a previous basilica of the 4th century which contained the body of Saint Saturnin or Sernin, the first bishop of Toulouse in c. 250.

The difficulty of determining an accurate chronology for the construction of Saint-Sernin and the completion of its sculpture has given rise to numerous problems.

At least as early as the 1010s, Bishop Pierre Roger had set aside a portion of the offerings to Saint-Sernin for an eventual rebuilding of the Carolingian church.

[4] Although there have been numerous attempts to determine the point that construction had reached at this time, the most that can be said with certainty is that 1096 is a firm terminus ante quem.

A 15th-century life of the saint states that he took charge of the building after part of the church had been completed and that by the time of his death he had "brought the walls all the way around up to the completion of the windows..."[5] However, the life was written much later—some three hundred years after the events it describes—and since at least three different Raymonds were involved in the building of the church, the biographer may have confused elements from the lives of all three.

While there is basic agreement on the starting point, interpretation of the subsequent archeological evidence is subject to varying opinions.

The plan of the abbey church here was also used in the construction of the cathedral of Santiago de Compostela, "begun in 1082, too direct a copy to have been done by any but Saint-Sernin's own architect or his favored pupil", but finished much earlier.

Another deviation from the earlier Christian churches is the addition of an ambulatory, a walkway that goes around the nave and side aisles to allow for viewing of the radiating chapels (which could be done while mass was being held without interrupting the ceremony).

The chevet is the oldest part of the building, constructed in the 11th century, and consists of nine chapels, five opening from the apse and four in the transepts.

The Porte Miègeville is known for its elaborate sculpture above the entrance: the ascending Christ, surrounded by superb angels, is the central figure on one of the oldest and most beautiful tympanums in Romanesque architecture (end of 11th c. or circa 1115).

Directly under the tower and the transept is a marble altar, consecrated by Pope Urban II in 1096 and designed by Bernard Gelduin.

Together with the Cavaillé-Coll instruments at Saint-Sulpice and the Church of St. Ouen, Rouen, it is considered to be one of the most important organs in France.