In the years 1931 to 1945 he was a professor in various provincial and Parisian lycees, and later at the University of Montpellier and Sorbonne where he worked until he retired in 1979.

Alquié's career was dominated by the decades-long polemic between himself as a Cartesian and the Spinozian perspective of his rival Martial Gueroult.

He was opposed to totalitarianism as well as to Marxism; as a close friend of André Breton, he aligned himself with the surrealist project.

He was an instructor of Gilles Deleuze, whom, according to Michael Hardt, he accused of drawing on biology, psychology, and other fields, neglecting philosophy.

Also among his students at the Sorbonne was the Finnish feminist philosopher and Descartes specialist Lilli Alanen.