Henri-Georges Clouzot was born in Niort, France, to mother Suzanne Clouzot and father Georges Clouzout, a book store owner. He was the first of three children in a middle-class family. Clouzot showed talent by writing plays and playing piano recitals. In 1922, Clouzot's father's bookstore went bankrupt and his family moved to Brest, France, where his father became an auctioneer. In Brest, Henri-Georges Clouzot went to Naval School, but was unable to become a Naval Cadet due to his myopia. At the age of 18, Clouzot left for Paris to study political science. While living in Paris, he became friends with several magazine editors. His writing talents led him to theater and cinema as a Playwright, lyricist and adaptor-screenwriter. The quality of his work led Producer Adolphe Osso to hire him and send him to Germany to work in Studio Babelsberg in Berlin, translating scripts for foreign language films shot there.

In the late-1930s, Clouzot went to a cabaret show featuring entertainers Mistinguett and Suzy Delair at the Deus Anes Cabaret. Clouzot waited for Delair at the stage door and after meeting her, the two became a romantic couple for the next 12 years. Clouzot had Delair star in two of his films, The Murderer Lives at Number 21 and Quai des Orfèvres. Delair eventually left Clouzot after working with him on Quai des Orfèvres.

In 1935, Clouzot was diagnosed with tuberculosis and was sent first to Haute-Savoie and then to Switzerland, where he was bedridden for nearly five years in all. Clouzot's time in the sanatorium would be very influential on his career. While bedridden, Clouzot read constantly and learned the mechanics of storytelling to help improve his scripts. Clouzot also studied the fragile nature of the other people in the sanatorium. Clouzot had little money during this period, and was provided with financial and moral support by his family and friends. By the time Clouzot left the sanatorium and returned to Paris, World War II had broken out. French cinema had changed because many of the producers he had known had fled France to escape Nazism.

Clouzot's health problems kept him from military Service. In 1939, he met actor Pierre Fresnay, who was already an established film star in France. Clouzot wrote the script for Fresnay's only directorial feature Le Duel, as well as two plays for him: On prend les mêmes, which was performed in December 1940, and Comédie en trois actes, which was performed in 1942. Despite writing scripts for films and plays, Clouzot was so poor that he resorted to trying to sell lyrics to French singer Édith Piaf, who declined to purchase them. After France was invaded by Germany and subsequently during the German occupation of France during World War II, the German-operated film production company Continental Films was established in France in October 1940. Alfred Grevin, the Director of Continental, knew Clouzot from Berlin and offered him work to adapt stories of Writer Stanislas-André Steeman. Clouzot felt uncomfortable working for the Germans, but was in desperate need of money and could not refuse Grevin's offer. Clouzot's first film for Continental was the adaptation of Steeman's mystery novel Six hommes mort (Six Dead Men). Clouzot retitled the film Le Dernier des six, having been influenced by Actress Suzy Delair while writing the script, allowing her to choose the name of the character she would play.

After the ban was lifted, Clouzot reestablished his reputation and popularity in France during the late 1940s with successful films including Quai des Orfèvres. After the release of his comedy film Miquette et sa mère, Clouzot married Véra Gibson-Amado, who would star in his next three feature films. In the early and mid-1950s, Clouzot drew acclaim from international critics and audiences for The Wages of Fear and Les Diaboliques. Both films would serve as source material for remakes decades later. After the release of La Vérité, Clouzot's wife Véra died of a heart attack and Clouzot's career suffered due to depression, illness and new critical views of films from the French New Wave. Clouzot's career became less active in later years, limited to a few television documentaries and two feature films in the 1960s. Clouzot wrote several unused scripts in the 1970s and died in Paris in 1977.

After the success of Le Dernier de six, Clouzot was hired as the head of Continental's screenwriting division. Clouzot began work on his second Steeman adaptation, which he would also direct, titled The Murderer Lives at Number 21. It starred Fresnay and Delair playing the same roles they had performed in Le Dernier de six. Released in 1942, the film was popular with audiences and critics. Clouzot's next film was Le Corbeau based on a true story about a woman who sent poison pen letters in France in 1922. Grevin was against Clouzot making this film, stating that topic was "dangerous". Le Corbeau would be the last film that Fresnay and Clouzot would work together on. Clouzot had used all possible means to try to anger the actor during the filming, and after he quarreled with Fresnay's wife, Yvonne Printemps, Fresnay and Clouzot broke off their friendship.Le Corbeau was a great success in France, with nearly 250,000 people having seen it in the first months of its initial release. Le Corbeau was released in 1943 and generated controversy from the right-wing Vichy regime, the left-wing Resistance press and the Catholic Church. The Catholic Church considered the film "painful and hard, constantly morbid in its complexity". The Vichy press dubbed it the antithesis of the Révolution nationale and demanded it be banned due to its immoral values. The anti-Nazi resistance press considered it Nazi propaganda because of its negative portrayal of the French populace. Two days before the release of Le Corbeau, Continental films fired Clouzot.

Clouzot was an early fan of the cinema and, desiring a career as a Writer, moved to Paris. He was later hired by Producer Adolphe Osso to work in Berlin, writing French-language versions of German films. After being fired from German studios due to his friendship with Jewish producers, Clouzot returned to France, where he spent years bedridden after contracting tuberculosis. Upon recovering, Clouzot found work in Nazi occupied France as a Screenwriter for the German-owned company Continental Films. At Continental, Clouzot wrote and directed films that were very popular in France. His second film Le Corbeau drew controversy over its harsh look at provincial France and Clouzot was fired from Continental before its release. As a result of his association with Continental, Clouzot was barred by the French government from filmmaking until 1947.

After Clouzot's ban was lifted, he reestablished his reputation and popularity in France during the late 1940s with films such as Quai des Orfèvres and Manon. For Quai des Orfèvres, Clouzot asked the author Stanislas-André Steeman for a copy of his novel, Légitime défense, to adapt into a film. Clouzot started writing the script before the novel arrived for him to read. Quai des Orfèvres was released in 1947 and was the fourth most popular film in France, drawing 5.5 million spectators in that year. Clouzot directed and wrote two films that were released in 1949. For Manon, he wanted to cast unknown actors. He scoured schools to find an Actress for the lead role, and chose 17-year-old Cécile Aubry after viewing over 700 girls. Manon was released in 1948 and was watched by 3.4 million filmgoers in France as well as winning the Golden Lion at the Venice Film Festival. Clouzot directed and wrote the short film Le Retour de Jean, which was part of the anthology film Return to Life. Le Retour de Jean was influenced by the short period when Clouzot lived in Germany in the early 1930s and stars Louis Jouvet as a survivor of a concentration camp who finds a wounded Nazi war Criminal whom he interrogates and tortures. Clouzot's next film was the comedy Miquette et Sa Mère, which was a financial failure. During the film's production, Clouzot met Véra Gibson-Amado, whom he married on 15 January 1950. Clouzot and Véra took a film crew with them to Véra's homeland in Brazil for their honeymoon, where Clouzot made his first attempt at directing a documentary film. The Brazilian government took issue with Clouzot filming the poverty of people in the favelas rather than the more picturesque parts of Brazil. The film was never finished because the costs became too high. Clouzot became fascinated with the region and wrote a book, Le cheval des dieux, recounting his trip.

Several of Clouzot's films have been remade since their original releases. Director Otto Preminger adapted Le Corbeau into his 1951 film, The 13th Letter. In 1977, the year of Clouzot's death, william Friedkin directed a remake of The Wages of Fear called Sorcerer. French Director Claude Chabrol adapted Clouzot's script for L'Enfer in 1994 also titled L'Enfer. In 1996, an American remake of Les Diaboliques was released under the title Diabolique, starring Sharon Stone.

Clouzot's next feature film was Les Espions, which was released in 1957. Les Espions featured actors from around the world including Véra Clouzot, Curd Jürgens, Sam Jaffe and Peter Ustinov. Les Espions would be the last acting role for Clouzot's wife Véra, who had been suffering from severe heart problems since filming Diabolique. Les Espions is set in a rundown sanitarium that is taken over by international spies. One of the spies claims to have invented a nuclear explosive device which attracts the attention of the Russian and American counterspies. Les Espions was not released in the United States and was a financial failure in France. Clouzot later admitted that he only liked the first two-thirds of Les Espions. Producer Raoul Levy suggested Clouzot's next film should feature Brigitte Bardot as the lead Actress. In response, Clouzot wrote the script for La Vérité. Bardot plays Dominique Marceau, who is on trial for the murder of her former boyfriend Gilbert Tellier. As her trial progresses, the relationship between Dominique and Gilbert becomes more finely shaped. Bardot later described La Vérité as her favorite of all the films she worked on. Released in 1960, La Vérité was the second most popular film in France with 5.7 million spectators and was Bardot's highest-grossing film. The film was nominated for the Academy Award for Best Foreign Language Film.

Clouzot met his first wife Vera Clouzot through actor Léo Lapara, who had minor parts in Le Retour de Jean and Quai des Orfèvres. Véra met Clouzot after divorcing Lapara and while working as a continuity assistant on Clouzot's Miquette et Sa Mère. Clouzot named his production company after Véra and had her star in all three films made by the company: The Wages of Fear, Diabolique and Les Espions. Véra also contributed to the script of La Vérité. Véra Clouzot died of a heart attack shortly after the filming of La Vérité. Clouzot fell into a depression over her death. After her funeral, he moved to Tahiti, but returned to France in December 1960.

Clouzot met his second wife, Inès de Gonzalez, for the first time at a casting call for a film based on Vladimir Nabokov's Laughter in the Dark. In 1962, Clouzot met de Gonzalez again after she had returned from South America. In December 1963, Clouzot and Inès de Gonzalez married. In the 1960s, Clouzot converted to Roman Catholicism.

Although Clouzot's reputation had grown internationally, he lost notability in French cinema due to rise of the French New Wave. The New Wave Directors refused to take Clouzot's thriller films seriously, and expressed their displeasure publicly through articles and reviews in the film criticism publication, Cahiers du cinéma. Clouzot took their criticism to heart, saying in the magazine Lui that he didn't find his films Diabolique and Miquette et Sa Mère important or interesting anymore. The next film he worked on was L'Enfer, which was never completed. The film examines the sexual jealousy of a man towards his flirtatious wife, whose psychological state deforms everything with Desire. Lead actor Serge Reggiani fell ill one week after shooting began and had to be replaced. Clouzot himself also became ill during production, which led doctors and insurance agents to order the production be stopped. Between 1965 and 1967, Clouzot filmed for French television five documentaries of Herbert von Karajan conducting Verdi's Requiem, Dvořák's New World Symphony, Schumann's 4th Symphony, Beethoven's 5th Symphony and Mozart's 5th Violin Concerto. After production finished on the documentaries, Clouzot was able to Finance his final picture.

Clouzot's return to work reassured the doctors and insurers and he returned to the film studio to make his final film La Prisonnière. The film began production in September 1967 and was halted when Clouzot fell ill and was hospitalized until April 1968. He began filming La Prisonnière again in August 1968. Clouzot incorporated stylistic elements of his aborted film L'enfer into La Prisonnière. La Prisonnière is about a woman who is introduced to a Photographer who takes masochistic submissive pictures of young women. The woman volunteers herself as a model for these pictures and is surprised at her own pleasure in the activity. After finishing La Prisonnière, Clouzot's health grew worse. In the 1970s, he wrote a few more scripts without ever filming them, including a feature about Indochina. He also planned to direct a pornographic film in 1974 for Francis Micheline, but the film was abandoned. Clouzot's health grew worse and he required open-heart surgery in November 1976. On 12 January 1977 Clouzot died in his apartment while listening to The Damnation of Faust. Clouzot is buried beside Véra in the Montmartre Cemetery.