He has worked with Jean-Luc Godard, Agnès Varda, and Jacques Rivette, as well as other notable directors such as Jean Cocteau, Pier Paolo Pasolini, Bernardo Bertolucci, Catherine Breillat, Jerzy Skolimowski, and Aki Kaurismäki.

Born in Paris, Léaud made his major debut as an actor at the age of 14 as Antoine Doinel, a semi-autobiographical character based on the life events of French film director François Truffaut, in The 400 Blows.

To cast the two central characters, Antoine Doinel and his partner-in-crime René Bigey, Truffaut published an announcement in France-Soir and auditioned several hundred children in September and October 1958.

[1]: 130 Throughout the production of The 400 Blows (Les Quatre Cents Coups, 1959), wrote Jay Carr, "Truffaut would take Léaud to see rushes of Godard's Breathless each evening.

[4] Léaud starred in four more Truffaut films depicting the life of Doinel, spanning a period of 20 years—after the short-film Antoine et Colette in 1962—beside actress Claude Jade as his girlfriend, and then wife, Christine.

"[2] He also collaborated with Truffaut on non-Antoine Doinel films like Two English Girls (Les Deux Anglaises et le Continent, 1971) and Day for Night (La Nuit américaine, 1973) and became the actor most commonly affiliated with him.

The early 1970s was perhaps the peak of his professional career when he had three critically acclaimed films released: Bertolucci's Last Tango in Paris (1972), Truffaut's La Nuit américaine, and Eustache's The Mother and the Whore (both 1973).

Léaud acted in films by other influential directors, such as Pier Paolo Pasolini, Jerzy Skolimowski, Aki Kaurismäki, Olivier Assayas, Tsai Ming-liang, Bertrand Bonello and Albert Serra.