La Mothe Le Vayer became an avocat in the Parlement of Paris, taking over his father's seat, but soon resigned when the attraction of belles lettres became stronger. His work La Contrariété d'humeur entre la nation française et l'espagnole (1636; “Conflicts of Interest Between the French and Spanish Nations”) and Considérations sur l'éloquence française (1638) earned him admission to the Académie Française in 1639. He was admired by the powerful Cardinal de Richelieu and was tutor to several noble youths, including from 1652 to 1657 Louis XIV, for whom he wrote a complete series of texts. The king rewarded him by appointing him historiographer of France and councillor of state.

His many philosophical works include De la vertu des païens (1642; “On the Goodness of the Pagans”); a treatise entitled Du peu de certitude qu'il y a dans l'histoire (1668; “On the Lack of Certitude in History”), which marked a beginning of historical criticism in France; and five skeptical Dialogues, published posthumously under the pseudonym Orosius Tubero, which are concerned, respectively, with diversity in opinions, variety in customs of life and sex roles, the value of solitude, the virtue of the fools of his time, and differences in religion.