His most famous work is the Panthéon in Paris, built from 1755 onwards, originally as a church dedicated to Saint Genevieve.

After returning to France, Soufflot practiced in Lyon, where he built the Hôtel-Dieu, like a chaste riverside street facade, interrupted by the central former chapel, its squared dome with illusionistic diminishing coffers on the interior.

Soufflot's newly made loggia is an unusually severe arcading tightly bound between flat Doric pilasters, with emphatic horizontal lines.

The Panthéon is his most famous work, but the Hôtel Marigny built for his young patron (1768–1771) across from the Élysée Palace, is a better definition of Soufflot's personal taste.

He stood out for his "strictness of line, firmness of form, simplicity of contour, and rigorously architectonic conception of detail"[1] which contrasted sharply with the late Baroque and Rococo architecture of his contemporaries.