He was named the second Greatest Male Star of All Time by the American Film Institute. His popular classic films include The Awful Truth (1937), Bringing Up Baby (1938), Gunga Din (1939), Only Angels Have Wings (1939), His Girl Friday (1940), The Philadelphia Story (1940), Suspicion (1941), Arsenic and Old Lace (1944), Notorious (1946), To Catch A Thief (1955), An Affair to Remember (1957), North by Northwest (1959), and Charade (1963).

At the 42nd Academy Awards the Academy of Motion Picture Arts and Sciences honored him with an Honorary Award "for his unique mastery of the art of screen acting with the respect and affection of his colleagues".

Archibald Alexander Leach was born in Horfield, Bristol, to Elsie Maria Kingdon (1877–1973) and Elias James Leach (1873–1935). An only child, he had an unhappy childhood, attending Bishop Road Primary School. His mother had suffered from depression since the death of a previous child. His father placed her in a mental institution, and told his nine-year-old son only that she had gone away on a "long holiday"; it was not until he was in his thirties that Grant discovered her alive, in an institutionalized care facility.

He was expelled from the Fairfield Grammar School in Bristol in 1918. He subsequently joined the "Bob Pender stage troupe" and travelled with the group to the United States as a stilt walker in 1920 at the age of 16, on a two-year tour of the country. He was processed at Ellis Island on July 28, 1920. When the troupe returned to the UK, he decided to stay in the U.S. and continue his stage career.

Still using his birth name, he performed on the stage at The Muny in St. Louis, Missouri, in such shows as Irene (1931); Music in May (1931); Nina Rosa (1931); Rio Rita (1931); Street Singer (1931); The Three Musketeers (1931); and Wonderful Night (1931).

After some success in light Broadway comedies, he went to Hollywood in 1931, where he acquired the name Cary Lockwood. He chose the name Lockwood after the surname of his character in a recent play called Nikki. He signed with Paramount Pictures, but while studio bosses were impressed with him, they were less than impressed with his adopted stage name. They decided that the name Cary was acceptable, but Lockwood had to go due to a similarity with another actor's name. It was after browsing through a list of the studio's preferred surnames, that Cary Grant was born. Grant chose the name because the initials C and G had already proved lucky for Clark Gable and Gary Cooper, two of Hollywood's biggest movie stars.

Already having appeared as leading man opposite Marlene Dietrich in Blonde Venus (1932), his stardom was given a further boost by Mae West when she chose him for her leading man in two of her most successful films, She Done Him Wrong and I'm No Angel (both 1933). I'm No Angel was a tremendous financial success and, along with She Done Him Wrong, which was nominated for an Academy Award for Best Picture, saved Paramount from bankruptcy. Paramount put Grant in a series of unsuccessful films until 1936, when he signed with Columbia Pictures. His first major comedy hit was when he was loaned to Hal Roach's studio for the 1937 Topper (which was distributed by MGM).

Grant starred in some of the classic screwball comedies, including Bringing Up Baby (1938) with Katharine Hepburn, His Girl Friday (1940) with Rosalind Russell, Arsenic and Old Lace (1944) featuring Priscilla Lane, and Monkey Business (1952) opposite Ginger Rogers and Marilyn Monroe. Under the tutelage of director Leo McCarey, his role in The Awful Truth (1937) with Irene Dunne was the pivotal film in the establishment of Grant's screen persona. These performances solidified his appeal, but it was The Philadelphia Story (1940), with Hepburn and James Stewart, that made him a star.

Grant was one of Hollywood's top box-office attractions for several decades. He was a versatile actor, who did demanding physical comedy in movies such as Gunga Din (1939) with the skills he had learned on the stage. Howard Hawks said that Grant was "so far the best that there isn't anybody to be compared to him".

Grant was a favorite actor of Alfred Hitchcock, notorious for disliking actors, who said that Grant was "the only actor I ever loved in my whole life". Grant appeared in the Hitchcock classics Suspicion (1941), Notorious (1946), To Catch a Thief (1955) and North by Northwest (1959). Biographer Patrick McGilligan wrote that, in 1965, Hitchcock asked Grant to star in Torn Curtain (1966), only to learn that Grant had decided to retire after making one more film, Walk, Don't Run (1966); Paul Newman was cast instead in Torn Curtain, opposite Julie Andrews.