DeMille's parents met as members of a music and literary society in New York. Henry was a tall, red-headed student. Beatrice was intelligent, educated, forthright, and strong-willed. They were both born in 1853 and both loved the theater. When they married, Beatrice converted to Henry's faith. Henry worked as a Playwright, administrator, and faculty member during the early years of The American Academy of Dramatic Arts, established in New York City in 1884. He built a house for his family in Wayne, New Jersey.

In 1893, at the age of forty, Henry de Mille contracted typhoid fever and died suddenly, leaving Beatrice with three children, a house, and no savings. Beatrice had "enthusiastically supported" her husband's theatrical aspirations. In his eulogy, she wrote:

DeMille began his career as an actor on the Broadway stage in the theatrical company of Charles Frohman in 1900. His brother william was establishing himself as a Playwright and sometimes invited him to collaborate. DeMille performed on stage with actors whom he would later direct in films: Charlotte Walker, Mary Pickford, and Pedro de Cordoba. DeMille also produced and directed plays. DeMille found success in the spring of 1913 producing Reckless Age by Lee Wilson, a play about a high society girl wrongly accused of manslaughter starring Frederick Burton and Sydney Shields. DeMille and his brother at times worked with the legendary impresario David Belasco, who had been a friend and collaborator of their father. Changes in the theater rendered DeMille's melodramas obsolete before they were produced, and true theatrical success eluded him. By 1913 he was having difficulty supporting his wife and baby daughter.

DeMille married Constance Adams on August 16, 1902 and had one child, Cecilia. The couple also adopted an orphan child, Katherine Lester, in the early 1920s; her father had been killed in World War I and her mother had died of tuberculosis.

In July 1913 DeMille, Jesse Lasky, Sam Goldfish (later Samuel Goldwyn), and a group of East Coast businessmen created the Jesse L. Lasky Feature Play Company. On December 12, 1913, DeMille, his cast, and crew boarded a Southern Pacific train bound for Flagstaff via New Orleans. His tentative plan was to shoot a film in Arizona, but he disliked the quality of light he saw there. He continued to Los Angeles. Once there, he chose not to shoot in Edendale, where many studios were, but in Hollywood. He also flouted the dictum that a film should run twenty minutes. He made his first film run sixty minutes, as long as a short play. The Squaw Man (1914), co-directed by Oscar Apfel, was a sensation and it established the Lasky Company.

DeMille made seventy features. In spite of careful storage in his film vaults, seven films were lost to nitrate decomposition; all were early silent films. The titles are: The Arab, The Wild Goose Chase, Chimmie Fadden, The Dream Girl, We Can't Have Everything, The Devil Stone, and The Squaw Man (the 1918 remake). Roughly twenty of his silent features are available in commercial DVD format.

After five years and thirty hit films, DeMille became the American film industry's most successful Director. In the silent era, he was renowned for Male and Female (1919), Manslaughter (1921), The Volga Boatman (1926), and The Godless Girl (1928). DeMille's trademark scenes included bathtubs, lion attacks, and Roman orgies. A number of his films featured scenes in two-color Technicolor.

The family spent time in Pompton Lakes, New Jersey, operating a private school in that town and attending Christ Episcopal Church. DeMille recalled that this church was the place where he visualized the story of his 1923 version of The Ten Commandments. Henry read to his children nightly, both from the classics and from the Bible. DeMille studied Scripture his entire life and read the Bible during lunch in the studio commissary. He was the first to admit that he did not attend church services but he did profess an unshakable belief in prayer. He stated that his films were a continuation of his father's work. "My ministry," said DeMille, "has been to make religious movies and to get more people to read the Bible than anyone else ever has."

In 1927, he directed The King of Kings, a biography of Jesus of Nazareth, which was acclaimed for its sensitivity and reached more than 800 million viewers. The Sign of the Cross (1932) was the first sound film to integrate all aspects of cinematic technique. Cleopatra (1934) was his first film to be nominated for the Academy Award for Best Picture. After more than thirty years in film production, DeMille reached the pinnacle of his career with Samson and Delilah (1949), a biblical epic which did "an all-time record Business." Along with biblical and historical narratives, he also directed films oriented toward "neo-naturalism," which tried to portray the laws of man fighting the forces of nature.

When "talking pictures" were innovated in 1928, DeMille made a successful transition, offering his own innovations to the painful process; he devised a microphone boom and a soundproof camera blimp. He also popularized the camera crane.

2. The films he made at Paramount between 1932 and 1947 were sold by that company to EMKA, Ltd. in 1957, and are available through the television division of NBCUniversal.

DeMille was one of the first Directors to become a Celebrity in his own right. He cultivated the image of the omnipotent Director, complete with megaphone, riding crop, and jodhpurs. From 1936 to 1944, DeMille hosted Lux Radio Theater, a weekly digest of current feature films.

Katherine became an Actress at Paramount Pictures, ultimately gaining his approval. In 1937 she married actor Anthony Quinn. In the 1920s the DeMilles adopted two sons, John and Richard, the latter of whom became a notable filmmaker, Writer, and Psychologist.

Because of his illness, DeMille asked his son-in-law, actor Anthony Quinn, to direct a remake of his 1938 film The Buccaneer. DeMille served as executive Producer. Despite a cast led by Charlton Heston and Yul Brynner, the 1958 film The Buccaneer was a disappointment.

In the 1940s, DeMille continued to please the public. He averaged one film a year; most of them centered on historical figures or Bible stories. His first attempt at a drama set within a semi-documentary frame was The Greatest Show on Earth, a saga of circus performers released in 1952. His experiment gained him a nomination for best Director and won an Academy Award for Best Picture that year.

DeMille was a lifelong conservative Republican Activist. He greatly admired Herbert Hoover. In 1944, he was the master of ceremonies at the massive rally organized by David O. Selznick in the Los Angeles Coliseum in support of the Dewey-Bricker ticket as well as Governor Earl Warren of California, who would become Dewey's running mate in 1948 and later the Chief Justice of the United States. The gathering drew 93,000, with short speeches by Hedda Hopper and Walt Disney. Among those in attendance were Ann Sothern, Ginger Rogers, Randolph Scott, Adolphe Menjou, Gary Cooper, and Walter Pidgeon. Though the rally drew a good response, most Hollywood celebrities who took a public position sided with the Roosevelt-Truman ticket.

In the early 1950s, DeMille was recruited by Allen Dulles and Frank Wisner to serve on the board of the anti-communist National Committee for a Free Europe, the public face of the organization that oversaw the Radio Free Europe Service.

He went on to receive his first nomination for the Academy Award for Best Director for his circus drama The Greatest Show on Earth (1952), which won both the Academy Award for Best Picture and the Golden Globe Award for Best Motion Picture – Drama. His last and most famous film, The Ten Commandments (1956), also a Best Picture Academy Award nominee, is currently the seventh-highest-grossing film of all time, adjusted for inflation. In addition to his Best Picture Award, he received an Academy Honorary Award for his film contributions, the Palme d'Or (posthumously) for Union Pacific, a DGA Award for Lifetime Achievement, and the Irving G. Thalberg Memorial Award. He was also the first recipient of the Golden Globe Cecil B. DeMille Award, which was later named in his honor.

In 1954, he was seeking approval for a lavish remake of his 1923 silent film The Ten Commandments. He went before the Paramount board of Directors, which was mostly Jewish-American. The members rejected his proposal, even though his last two films, Samson and Delilah and The Greatest Show on Earth, had been record-breaking hits. Adolph Zukor, the chairman of the board, rebuked the members, saying:

In the early hours of January 21, 1959, DeMille died of a heart ailment.

Two schools have been named after him: Cecil B. DeMille Middle School, in Long Beach, California, closed and demolished in 2007 to make way for a new high school; and Cecil B. DeMille Elementary School in Midway City, California.

DeMille drew on his Christian and Jewish heritage to convey a message of tolerance. The Crusades was the first film to show accord between Christians and Muslims. DeMille received more than a dozen awards from Jewish religious and cultural groups, including B’nai B’rith.