Le Lionnais was born in Paris on 3 October 1901. Trained as a chemical engineer, he directed the Forges d'Aquiny industrial firm during the years 1928-1929. Active in the French resistance group Front National during World War II, he was arrested and tortured by the Gestapo in October 1944 and spent six months (November 1944-April 1945) as a prisoner in the Dora concentration camp. His 1946 essay “La Peinture à Dora” (“Painting in Dora”) describes his experience as a prisoner.
After World War II, Le Lionnais became the director of General Studies at the École Supérieure de Guerre (now part of the École Militaire). In 1950 he became the founding head of the Division of Science Education at UNESCO.
Together with the French physicist Louis de Broglie and his close friend Jacques Bergier, Le Lionnais co-founded the Association of French Science Writers on 26 June 1950. Le Lionnais served as the first president of the association, which was initially funded by UNESCO.
In 1952, again working with Jacques Bergier, Le Lionnais created UNESCO’s Kalinga-UNESCO Prize for excellence in the popularization of science. The first recipient was Louis de Broglie. In the following decade, Le Lionnais joined an advisory committee on scientific terminology to the French Academy of Sciences, acted as a scientific consultant to the Commission for Restoration of Works of Art in French national museums, and served as a technical expert to India's council on scientific research. He produced and hosted a popular-science program, “La Science en Marche,” for the France Culture radio station.
Le Lionnais was active in experimental and absurdist artistic movements, as Regent of the Collège de ‘Pataphysique and as co-founder and first president of Oulipo. Oulipo was founded in 1960 with Raymond Queneau and later augmented, by Le Lionnais and others, with a series of analogous organizations including Oulipopo (detective fiction), Oumupo (music), Oupeinpo (painting), Oucinépo (film), and Oucuipo (cooking).