In his youth Lescot, who came from a wealthy family of lawyers, studied mathematics, architecture, and painting. There is no evidence that he visited Italy, although much of his design was classical; it appears that he acquired his knowledge of architecture from illustrated books and from Roman ruins in France.

Lescot's most important contribution to architecture was his rebuilding of the Louvre (Louvre Museum), which he began in 1546 as a commission from Francis I. The style and design of Lescot's work on the Louvre reflect a revolution in French architecture marked by the influence of classical elements. His work on the facade combined traditional French elements and classical features to create a unique style of French classicism. Lescot's other work includes the Hôtel Carnavalet (1545), which still survives in part; a screen at Saint-Germain-l'Auxerrois (1554); the Fontaine des Innocents (1547–49); and the château of Vallery. Unfortunately, none of these works has survived intact.