Gable was born in Cadiz, Ohio to William Henry "Bill" Gable and Adeline Hershelman, of German and Irish descent. He was mistakenly listed as a female on his birth certificate. His original name was probably William Clark Gable, but birth registrations, school records and other documents contradict one another. "William" would have been in honor of his father. "Clark" was the maiden name of his maternal grandmother. In childhood he was almost always called "Clark"; some friends called him "Clarkie," "Billy," or "Gabe".

When he was six months old, his sickly mother had him baptized Roman Catholic. She died when he was ten months old, probably of an aggressive brain tumor.

In April 1903, Gable's father Will married Jennie Dunlap, whose family came from the small neighboring town of Hopedale. Gable was a tall shy child with a loud voice. After his father purchased some land and built a house, the new family settled in. Jennie played the piano and gave her stepson lessons at home; later he took up brass instruments. She raised Gable to be well-dressed and well-groomed; he stood out from the other kids. Gable was very mechanically inclined and loved to strip down and repair cars with his father. At thirteen, he was the only boy in the men's town band. Even though his father insisted on Gable doing manly things, like hunting and hard physical work, Gable loved language. Among trusted company, he would recite Shakespeare, particularly the sonnets.

At seventeen, Gable was inspired to be an actor after seeing the play The Bird of Paradise, but he was not able to make a real start until he turned 21 and inherited money. His acting coach was a theater manager in Portland, Oregon, Josephine Dillon (17 years his senior). Dillon paid to have his teeth repaired and his hair styled. In 1924, with Josephine Dillon's financial aid, they went to Hollywood, where she became his manager and first wife. He changed his stage name from W. C. Gable to Clark Gable. He found work as an extra in such silent films as The Plastic Age (1925), which starred Clara Bow, and Forbidden Paradise, plus a series of two-reel comedies called The Pacemakers. He also appeared as a bit player in a series of shorts. However, Gable was not offered any major roles and so he returned to the stage. During the 1927-28 theater season, Gable acted with the Laskin Brothers Stock Company in Houston, where he played many roles, gained considerable experience and became a local matinee idol. Gable then moved to New York and Dillon sought work for him on Broadway.

In 1930, after his impressive appearance as the seething and desperate character Killer Mears in the play The Last Mile, Gable was offered a contract with MGM. His first role in a sound picture was as the villain in a low-budget William Boyd western called The Painted Desert (1931).

In 1930, Gable and Josephine Dillon were divorced. A few days later, he married Texas socialite Ria Franklin Prentiss Lucas Langham. After moving to California, they were married again in 1931, possibly due to differences in state legal requirements.

Gable's timing in arriving in Hollywood was excellent as MGM was looking to expand its stable of male stars and he fit the bill. Gable then worked mainly in supporting roles, often as the villain.

Gable won the Academy Award for Best Actor for his lead role of Peter Warne in It Happened One Night. Gable also earned an Academy Award nomination when he portrayed Fletcher Christian in 1935's Mutiny on the Bounty. In the following years, he acted in a succession of enormously popular pictures, earning him the undisputed title of "King of Hollywood" in 1938.

Despite his reluctance to play the role, Gable is best known for his performance in Gone with the Wind (1939), which earned him an Academy Award nomination for Best Actor.

Other memorable performance were in Run Silent, Run Deep, a classic submarine film, and his final film The Misfits (1961), which paired Gable with Marilyn Monroe in one of her last roles.

In his long film career, Gable was paired with some of the best and most popular actresses of the time. Joan Crawford, who was his favorite actress to work with, was partnered with Gable in eight films, Myrna Loy was with him seven times, and he played opposite Jean Harlow in six productions. He also starred with Lana Turner in four features, and with Norma Shearer in three.

Gable died in Los Angeles, California on November 16, 1960, the result of a fourth heart attack.