Laemmle was in the habit of coming to Europe each year, searching for promising young men who would work in America. In 1921, Wyler, while traveling as a Swiss citizen (his father’s status automatically conferred Swiss citizenship to his sons), met Laemmle who hired him to work at Universal Studios in New York. As Wyler said: “America seemed as far away as the moon.” Booked onto a ship to New York with Laemmle upon his return voyage, he met a young Czech man, Paul Kohner (later the famous independent agent), aboard the same ship. Their enjoyment of the first class trip was short-lived, however, as they found they had to pay back the cost of the passage out of their $25 weekly income as messengers to Universal Pictures. After working in New York for several years, and even serving in the New York Army National Guard for a year, Wyler moved to Hollywood to become a director.

Around 1923, Wyler arrived in Los Angeles and began work on the Universal Studios lot in the swing gang, cleaning the stages and moving the sets. His break came when he was hired as a second assistant editor. But his work ethic was uneven, and he would often sneak off and play billiards in a pool hall across the street from the studio, or organize card games during working hours. After some ups and downs (including getting fired), Wyler focused on becoming a director and put all his effort into it. He started as a third assistant director and by 1925 he became the youngest director on the Universal lot directing the westerns that Universal was famed for turning out. Wyler was so focused on his work that he would dream about “different ways (for an actor) to get on a horse”. In several of the one-reelers, he would join the posse in the inevitable chase of the ‘bad man’.

He directed his first non-Western, the lost Anybody Here Seen Kelly?, in 1928. This was followed by his first part-talkie films, The Shakedown and The Love Trap. He proved himself an able craftsman. In 1928 he became a naturalized United States citizen. His first all-talking film, and Universal’s first sound production to be filmed entirely on location, was Hell’s Heroes, filmed in the Mojave Desert in 1929.

Director and screenwriter John Huston had been a close friend of Wyler during his career. When he was twenty-eight and penniless, sleeping in parks in London, Huston returned to Hollywood to see if he could find work. Wyler, four years his senior, had met Huston when he was directing his father, Walter Huston, in A House Divided in 1931, and they got along well. Wyler read dialogue suggestions that Huston had given to his father Walter and hired John to work on the dialogue for the script. He later inspired Huston to become a director and became his “early mentor.” When America entered World War II in 1941, Wyler, Huston, Anatole Litvak and Frank Capra, by then all directors, enlisted at the same time. Later in his career, Huston recalled his friendship with Wyler during an interview:

Bette Davis received three Oscar nominations for her screen work under Wyler, and won her second Oscar for her performance in Wyler’s 1938 film Jezebel. She told Merv Griffin in 1972 that Wyler trained her with that film to be a “far, far better actress” than she had been. She recalled a scene that was only a bare paragraph in the script, but “without a word of dialog, Willy created a scene of power and tension. This was moviemaking on the highest plane,” she said. “A scene of such suspense that I never have not marveled at the direction of it.” During her acceptance speech when she received the AFI Life Achievement Award in 1977, she thanked him.

Wyler was briefly married to actress Margaret Sullavan (from November 25, 1934 – March 13, 1936) and married actress Margaret “Talli” Tallichet on October 23, 1938. The couple remained together until his death; they had five children: Catherine, Judith, William Jr., Melanie and David. Catherine said during an interview that her mother played an important part in his career, often being his “gatekeeper” and his reader of scripts presented to him.

In 1941, Wyler directed Mrs. Miniver, based on the 1940 novel; it was the story of a middle-class English family adjusting to the war in Europe and the bombing blitz in London. It starred Greer Garson and Walter Pidgeon. Pidgeon originally had doubts about taking on the role, until fellow actor Paul Lukas told him, “You will find working with Wyler to be the most delightful experience you ever had, and that’s the way it turned out.” Pidgeon recalls: “One thing that would have been a terrific regret in my life is if I had succeeded in getting out of doing Mrs. Miniver” He received his first Oscar nomination for his role, while his co-star, Greer Garson, won her first and only Academy Award for her performance.

However, before America entered the war in December 1941, all films that could be considered anti-Nazi were banned by the Hays Office.

Between 1942 and 1945 Wyler volunteered to serve as a major in the United States Army Air Forces and directed a pair of documentaries: The Memphis Belle: A Story of a Flying Fortress (1944), about a Boeing B-17 and its U.S. Army Air Force crew; and Thunderbolt! (1947), highlighting a P-47 fighter-bomber squadron in the Mediterranean. Wyler filmed The Memphis Belle at great personal risk, flying over enemy territory on actual bombing missions in 1943; on one flight, Wyler lost consciousness from lack of oxygen. Wyler’s associate, cinematographer Harold J. Tannenbaum, a First Lieutenant, was shot down and perished during the filming. Director Steven Spielberg describes Wyler’s filming of Memphis Belle in the 2017 Netflix series, Five Came Back.

Five years later, in 1944, while visiting London, Wyler met with Olivier and his actress wife, Vivien Leigh. She invited him to see her performance in The Doctor’s Dilemma, and Olivier asked him to direct him in his planned film, Henry V. But Wyler said he was “not a Shakespearian” and turned down the offer.

In 1949 Wyler directed The Heiress, which earned Olivia de Havilland her second Oscar and garnered additional Oscars for Best Art Direction, Best Costume Design, and Best Music. The film is considered by some to be a highlight in her career, “that could strike envy even in the most versatile and successful actress,” according to one critic.

In 1950, Wyler and Olivier made a second film together, Carrie, which was not a commercial success. However, some critics state that it nonetheless contains Olivier’s finest film performance, but because of its old-fashioned story, the film was very under-appreciated: In critic Michael Billington’s opinion:

In 1951, Wyler produced and directed Kirk Douglas and Eleanor Parker in Detective Story, portraying a day in the lives of the various people in a detective squad. Lee Grant and Joseph Wiseman made their screen debuts in the film, which was nominated for four Academy Awards, including one for Grant. Critic Bosley Crowther lauded the film, describing it as “a brisk, absorbing film by producer-director William Wyler, with the help of a fine, responsive cast.”

Kirk Douglas had lobbied Wyler, who directed him in Detective Story in 1951, for the title role, but only after Wyler had already decided on Heston. He offered him instead the role of Messala, which Douglas rejected. Douglas then went on to star in Spartacus (1960).

Carrie was released in 1952 starring Jennifer Jones in the title role and Laurence Olivier as Hurstwood. Eddie Albert played Charles Drouet. Carrie received two Academy Award nominations: Costume Design (Edith Head), and Best Art Direction (Hal Pereira, Roland Anderson, Emile Kuri). Wyler was reluctant to cast Jennifer Jones, and the filming was subsequently plagued by a variety of troubles. Jones had not revealed that she was pregnant; Wyler was mourning the death of his year-old son; Olivier had a painful leg ailment, and he developed a dislike for Jones. Hollywood was reeling under the effects of McCarthyism, and the studio was afraid to distribute a film that could be attacked as immoral. Ultimately, the ending was changed and the film was cut to make it more positive in tone.

Friendly Persuasion (1956) was awarded the Palme d’Or (Golden Palm) at the Cannes Film Festival. And in 1959, Wyler directed Ben-Hur, which won 11 Oscars, a feat unequaled until Titanic in 1997. He had also assisted in the production of the 1925 version.

For his contributions to the motion picture industry, on February 8, 1960, Wyler has a star on the Hollywood Walk of Fame at 1731 Vine Street.

In 1961, Wyler was chosen as one of 50 outstanding Americans of meritorious performance in the fields of endeavor, to be honored as a Guest of Honor to the first annual Banquet of the Golden Plate in Monterey, California. Honor was awarded by vote of the National Panel of Distinguished Americans of the Academy of Achievement.

Wyler’s films garnered more awards for participating artists and actors than any other director in the history of Hollywood. He received 12 Oscar nominations for Best Director, while dozens of his collaborators and actors won Oscars or were nominated. In 1965, Wyler won the Irving G. Thalberg Memorial Award for career achievement. Eleven years later, he received the American Film Institute Life Achievement Award. In addition to his Best Picture and Best Director Oscar wins, 13 of Wyler’s films earned Best Picture nominations. Other late Wyler films include The Children’s Hour (1961), which was nominated for five Academy Awards. Later films included The Collector (1963), Funny Girl (1968), and his final film, The Liberation of L.B. Jones (1970).

In 1968 he directed Barbra Streisand in her debut film, Funny Girl, costarring Omar Sharif, which became a huge financial success. It was nominated for eight Academy Awards, and like Audrey Hepburn in her first starring role, Streisand won as Best Actress, becoming the thirteenth actor to win an Oscar under his direction.

The last film Wyler directed was The Liberation of L.B. Jones, released in 1970.

He has the distinction of having directed more actors to Oscar-nominated performances than any other director in history: thirty-six. Out of these nominees, fourteen went on to win Oscars, also a record. He received the fourth AFI Life Achievement Award in 1976. Among those who thanked him for directing her in her debut film, was Barbra Streisand.

On July 24, 1981, Wyler gave an interview with his daughter, Catherine, for Directed by William Wyler, a PBS documentary about his life and career. Three days later, he died from a heart attack. He is interred at Forest Lawn Memorial Park Cemetery.

Many of Wyler’s home movies are held by the Academy Film Archive; the archive preserved a number of them in 2017.