Born Mikhail Anatol Litvak in Kiev, Kiev Governorate, Russian Empire, Litvak grew up in a Lithuanian Jewish family.. ("Litvak" means "Lithuanian" in Yiddish). As a teenager, he worked at a theater in St. Petersburg and took acting lessons at the state drama school. Litvak worked with Leningrad's Nordkino Studios where he was assistant Director for nine silent films. For political and ideological reasons, and especially because Russian theaters were nationalized in the 1920s, he fled Russia for Berlin in 1925.

The world-wide success of Mayerling brought Litvak invitations from Hollywood, including being offered a four-year contract by Warner Brothers. Accepting the contract, Litvak became one of Hollywood's leading Directors by the late 1930s. He directed such films as Tovarich, a comedy celebrating "outmoded values of the ruined Russian aristocracy."

As a result of having made Paris his home after fleeing Germany, the city would later become his favored locale for shooting films; thirteen of his thirty-seven films were set in Paris, including 1936's Mayerling. Max Ophüls, who worked as Litvak's assistant in France, would later become a recognized Director.

In 1937, Litvak became the third husband of American Actress Miriam Hopkins; their short-lived marriage ended in divorce in 1939. His second marriage was in 1955 to the model Sophie Steur. They remained married until his death.

Also with Warners, he directed Confessions of a Nazi Spy, a 1939 film starring Edward G. Robinson as an FBI agent who breaks up a Nazi spy ring. Among the techniques he used in the film to achieve realism was the inclusion of actual newsreel footage from U.S. Nazi rallies. While the story was fictional, the espionage methods that it exposed were considered factual and real, which led to the film being considered the "strongest and most thrilling dramatic movie" that had ever been put on screen. However, the film was banned in Germany, Italy and Spain, as well as neutral countries such as Switzerland and Ireland.

In 1940 he produced and directed All This and Heaven Too, starring Bette Davis and Charles Boyer. The film was nominated for an Academy Award as Best Picture. That same year he co-produced and directed City for Conquest, starring James Cagney and supporting actor Elia Kazan, in one of his few film roles before becoming a leading Director. The Hollywood Reporter gave Litvak's directing special praise:

Litvak became involved with helping the Soviet Union in August 1941, soon after it was invaded by Nazi Germany. He was treasurer of the Russian War Relief Association, which sponsored international radio benefits with stars such as Edward G. Robinson and Ronald Colman.

Litvak, having by then become an American citizen, enlisted in the United States Army at the beginning World War II, rising to the rank of lieutenant colonel. He joined with fellow Director Frank Capra to make the Why We Fight war training film series, most of which also included actual newsreel footage. Films they co-directed for the series included Prelude to War (1942), The Nazis Strike (1943), and Battle of China (1944). Capra was in charge of production for all the films.

He later directed Operation Titanic (1943), and War Comes to America (1945), the final film in the Why We Fight series. The films were scripted by Anthony Veiller and narrated by Walter Huston, with music by Dimitri Tiomkin, another Russian-born émigré to Hollywood. Prelude to War won the Oscar for Best Documentary of 1942. Because of Litvak's ability to speak Russian, German, and French, he subsequently supervised the filming of the D-Day Normandy landings. He also filmed aerial warfare with the U.S. Eighth Air Force.

Also in 1948, Litvak directed Barbara Stanwyck and Burt Lancaster in a noir thriller, Sorry, Wrong Number, a role which film Historian James Robert Parish says is Stanwyck's "greatest screen triumph." Litvak directed using a "variety of surrealistic and expressionistic devices," notes Film Noir magazine. "Litvak isn't afraid to use close-ups either. And his players not only stand up to this relentless probing but offer some of the greatest performances of their lives."

After the mid-1950s, Litvak began filming in Europe. Among his productions there was the Paris-filmed Anastasia in 1956, starring Ingrid Bergman, Yul Brynner and Helen Hayes. The film was Bergman's first U.S. film after a seven-year absence from Hollywood, which she left after her scandalous affair with Director Roberto Rossellini became news. The studio, Twentieth Century Fox, conducted a poll and found that the public still had negative feelings toward Bergman. Litvak, however, felt she would be an excellent Actress for the part and insisted on her starring in the film. Bergman won an Oscar for Best Actress for her part, and film critic Michael Barson calls it Litvak's best film of the 1950s.

In 1951, his war film, Decision Before Dawn, was nominated for an Academy Award for Best Picture. Thousands of French admirers of the film signed a huge scroll which they sent to AMPAS, insisting that the film be given an Oscar. It was Oskar Werner's first acting role in an American film.

As a refugee from Nazi Germany, Litvak tried to open Hollywood's eyes to the threat Germany posed to Europe and the world, explains biographer Alexander Walker. Actress Vivien Leigh, who would star in Litvak's The Deep Blue Sea (1955), recalls her Sunday morning visits to Litvak and his wife, Miriam Hopkins, where she would learn from him about the studios' efforts to protect their Investments in German box-office. Hollywood's "comfortable isolationism affronted her."

At the 1961 Cannes Film Festival, Litvak's Goodbye Again (also starring Ingrid Bergman) was nominated for the Palme d'Or. Before he retired, Litvak did two more films: The Night of the Generals, a movie about three Nazi Generals suspected of murder, starring Peter O'Toole and Donald Pleasence. Litvak said about the film's subdued tones, "We tried staying away from color as much as we could; color can be bad, particularly with the war; it takes away from reality in the most horrible way." In France and Poland, he later filmed The Lady in the Car with Glasses and a Gun.

Litvak died in 1974 in the Parisian suburb of Neuilly-sur-Seine.