Truffaut was immediately captivated by the fourteen-year-old adolescent, who had already appeared with Jean Marais in Georges Lampin's La Tour, prends garde ! (1958). He recognized traits they both shared, "for Example a certain suffering with regard to the family...With, however, this fundamental difference: though we were both rebels, we hadn't expressed our rebellion in the same way. I preferred to cover up and lie. Jean-Pierre, on the contrary, seeks to hurt, shock and wants it to be known...Why? Because he's unruly, while I was sly. Because his excitability requires that things happen to him, and when they don't occur quickly enough, he provokes them". In his final interview, Truffaut mentioned he was happy with how Léaud improvised within the flexibly written script.

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. They'd sit up late talking film with Godard, Rivette, Rohmer, Eustache, Orson Welles.” Upon the filmmaker’s death, the actor reminisced Truffaut was the first person he admired and that he “spoke to children like they were adults. He realized that children understood things better than adults did. He was purely intuitive. We operated in a sort of complicity.”

In March 1966, Léaud won the Silver Bear for Best Actor at the 16th Berlin International Film Festival for his role in Jean-Luc Godard's Masculin, féminin. He was nominated for a César Award for Best Supporting Actor in 1988 for Les Keufs and was awarded an Honorary César for lifetime achievement in 2000.

Léaud is one of the most visible and well-known actors to be associated with the French New Wave film movement and, aside from his work with Truffaut, collaborated with Jean-Luc Godard (nine films), Jean Eustache, Jacques Rivette and Agnes Varda. 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). In the Bertolucci film, Léaud appeared in the same film as a hero of his, Marlon Brando , although the two men never met, since all of Léaud's scenes were shot on Saturdays and Brando refused to work on Saturdays.

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. Those films are Stolen Kisses (1968), Bed and Board (1970) and Love on the Run (1979). Truffaut stated that Léaud was the source of inspiration for the Antoine Doinel character and "I created some scenes just because I knew he would be funny in them—at least I laughed during the writing as I thought of him." 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. Although Antoine Doinel is his most familiar character, he often found his performances in other films to be compared to his Doinel character whether there were legitimate similarities or not.

During and following the filming of The 400 Blows, Truffaut’s concern for Léaud extended beyond the film set. He took charge of the difficult adolescent’s upbringing after Léaud was expelled from school and kicked out of the home of the retired couple taking care of him. Truffaut subsequently rented a studio apartment for Léaud. Truffaut also hired him for assistant work on The Soft Skin (La peau douce, 1964) and Mata Hari, Agent H21 (1964).