Born in Paris, he attracted the notice of Chancellor Séguier, who placed him at the age of eleven in the studio of Simon Vouet. He was also a pupil of François Perrier. At fifteen he received commissions from Cardinal Richelieu, in the execution of which he displayed an ability which obtained the generous commendations of Nicolas Poussin, in whose company Le Brun started for Rome in 1642.

On his return to Paris in 1646, Le Brun found numerous patrons, of whom Superintendent Fouquet was the most important, for whom he painted a large portrait of Anne of Austria. Employed at Vaux-le-Vicomte, Le Brun ingratiated himself with Mazarin, then secretly pitting Colbert against Fouquet. Colbert also promptly recognized Le Brun's powers of organization, and attached him to his interests. Together they took control of the Academy of Painting and Sculpture (Académie royale de peinture et de sculpture, 1648), and the Academy of France at Rome (1666), and gave a new development to the industrial arts.

Another project Le Brun worked on was Hôtel Lambert. The ceiling in the gallery of Hercules was painted by him. Le Brun started work on the project in 1650, shortly after his return from Italy. The decoration continued intermittently over twelve years or so, as it was interrupted by the renovation of Vaux le Vicomte.

The nature of his emphatic and pompous talent was in harmony with the taste of the king, who, full of admiration of the paintings by Le Brun for his triumphal entry into Paris (1660) and his decorations at the Château Vaux le Vicomte (1661), commissioned him to execute a series of subjects from the history of Alexander. The first of these, "Alexander and the Family of Darius," so delighted Louis XIV that he at once ennobled Le Brun (December, 1662), who was also created Premier Peintre du Roi (First Painter of the King) with a pension of 12,000 livres, the same amount as he had yearly received in the Service of the magnificent Fouquet. The King had declared him "the greatest French Artist of all time".

From this date all that was done in the royal palaces was directed by Le Brun. In 1663, he became Director of the Académie royale de peinture et de sculpture, where he laid the basis of academicism and became the all-powerful, peerless master of 17th-century French art. It was during this period that he dedicated a series of works to the history of Alexander The Great (The Battles of Alexander The Great), and he did not miss the opportunity to make a stronger connection between the magnificence of Alexander and that of the great King. While he was working on The Battles, Le Brun's style became much more personal as he moved away from the ancient masters that influenced him.

The works of the gallery of Apollo in the Louvre were interrupted in 1677 when he accompanied the king to Flanders (on his return from Lille he painted several compositions in the Château de Saint-Germain-en-Laye), and finally—for they remained unfinished at his death—by the vast labours of Versailles, where he reserved for himself the Halls of War and Peace (Salons de la Guerreand de la Paix, 1686), the Ambassadors' Staircase, and the Great Hall of Mirrors (Galerie des Glaces, 1679–1684). Le Brun's decoration is not only a work of art, it is the definitive monument of a reign.

At the death of Colbert, François-Michel le Tellier, Marquis de Louvois, Colbert's enemy, who succeeded as superintendent in the department of public works, showed no favour to Le Brun who was Colbert's favorite, and in spite of the king's continued support Le Brun felt a bitter change in his position. This contributed to the illness which on 22 February 1690 ended in his death in his private mansion, in Paris.

In his posthumously published treatise, Méthode pour apprendre à dessiner les passions (1698), he promoted the expression of the emotions in painting. It had much influence on art theory for the next two centuries.

On 23 January 2013, artistic advisors for the Hôtel Ritz Paris, Wanda Tymowska and Joseph Friedman, announced the discovery of The Sacrifice of Polyxena, an early work of Le Brun. The picture, dated 1647, ornamented the Coco Chanel suite of the famous Parisian palace, and went unnoticed for over a century.