Blondel was born into a famous architectural family and was reared by an uncle. Though Blondel initially went along with the Rococo (Rococo style) ornamentation of the preceding age, he eventually turned against it. In 1737 he executed some plates for Pierre-Jean Mariette's edition of Augustin Daviler's 17th-century treatise on architecture, taking the opportunity to refine some designs of the Rococo woodcarver Nicolas Pineau (Pineau, Nicolas), who had earlier collaborated with his uncle. In the same year, Blondel's De la distribution des maisons de plaisance et de la décoration des édifices en général (2 vol., 1737–38; “On the Designing of Country Seats and on the Decoration of Buildings in General”) began to appear. The work, while not original, expressed an ideal of the taste that continued through the Enlightenment. Blondel's own buildings of the 1730s included an orangery near Florence, the terraces of a château near Brittany, and his town house, Petit dâ Marivat, at Besançon.

As a teacher, first in his own school (1743–54) and later at the Académie Royale d'Architecture, Blondel influenced such students as the Scottish architect William (later Sir William) Chambers (Chambers, Sir William), best known for his Somerset House for the Royal Academy of Arts in London (1776; later replaced); the French architect Richard Mique, who did much work for Marie-Antoinette at Versailles; the Dutch architect Pieter de Swart, who designed the only remaining Rotterdam gate, the Gate of Delft; and the German architect Christian Weinlig, a member of the Dresden Neoclassical school. In this period Blondel designed a comprehensive plan for the decoration of the centre of Metz (1764), including the Hôtel de Ville (1765).

At the invitation of Denis Diderot (Diderot, Denis) and Jean le Rond d'Alembert (Alembert, Jean Le Rond d'), Blondel wrote the architecture section for the Encyclopédie (1751–72), the work that set forth the rationalist philosophy of the Enlightenment. As his own significant contribution to 18th-century learning, Blondel compiled his lectures and plans in the monumental Cours d'architecture (1771–77; “Architecture Course”); the 12-volume work was completed (and its 6 volumes of plates combined into 3 volumes) by the French architect, writer, and engraver Pierre Patte.