In 1882 (a year after the actual gunfight at the O.K. Corral on October 26, 1881), Wyatt (Henry Fonda), Morgan (Ward Bond), Virgil (Tim Holt), and James Earp (Don Garner) are driving cattle to California, and encounter Old Man Clanton (Walter Brennan) and his sons, Billy (John Ireland) and Ike (Grant Withers). Clanton offers to buy their herd, but they curtly refuse to sell. When the Earps learn about the nearby boom town of Tombstone, the older brothers ride in, leaving the youngest, James, as watchman. The threesome soon learns that Tombstone is a lawless town without a marshal. Wyatt proves the only man in the town willing to face drunken Indian Charlie (Charles Stevens) shooting at the townspeople. When the brothers return to their camp, they find their cattle rustled and James murdered.

Wyatt returns to Tombstone. Seeking to avenge James's murder, he takes the open position of town marshal and encounters the hot-tempered Doc Holliday (Victor Mature) and scurrilous Clanton gang several times. Clementine Carter (Cathy Downs), Doc's former love interest, arrives from his hometown of Boston. Chihuahua (Linda Darnell), Doc's hot-tempered Latina love interest, sings in the local saloon. Doc, who is suffering badly from tuberculosis, is unhappy with her arrival. He tells her to return to Boston or he will leave Tombstone. Clementine stays, so Doc leaves for Tucson, Arizona. Wyatt notices Chihuahua is wearing a silver cross that had been taken from his brother, James, the night he'd been killed. She claims Doc gave it to her.

Wyatt chases down Doc, with whom he has had a testy relationship. Doc forces a shoot-out, ending with Wyatt shooting a pistol out of Doc's hand. The two return to Tombstone, where after being questioned, Chihuahua reveals the silver cross was actually given to her by Billy Clanton. During the interrogation Billy shoots Chihuahua through a window and takes off on horseback, but is wounded by Wyatt. Wyatt directs his brother Virgil to pursue him. The chase leads to the Clanton homestead, where Billy dies of his wounds. Old Man Clanton then shoots Virgil in the back in cold blood.

In town, a reluctant Doc is persuaded to operate on Chihuahua. Hope swells for her successful recovery. The Clantons then arrive, toss Virgil's body on the street and announce they will be waiting for the rest of the Earps at the O.K. Corral.

Chihuahua dies and Doc decides to join the Earps, walking alongside Wyatt and Morgan to the corral at sunup. A gunfight ensues in which all of the Clantons are killed, as is Doc.

Wyatt and Morgan resign as law enforcers. Morgan heads West in a horse and buggy. Wyatt bids Clementine farewell at the school house, wistfully promising that if he ever returns he will look her up. Mounting his horse, he muses aloud "Ma'am, I sure like that name...Clementine," and rides off to join his brother.

A 1946 American Black & White Western film directed by John Ford, produced by Samuel G. Engel, screenplay by Engel and Winston Miller, story by Sam Hellman, cinematography by Joseph MacDonald, starring Henry Fonda, Linda Darnell, Victor Mature, Cathy Downs, Walter Brennan, Tim Holt, Ward Bond, Don Garner, Grant Withers, John Ireland, Alan Mowbray, Roy Roberts, Jane Darwell, J. Farrell MacDonald, and Russell Simpson.

Much of the film was shot in Monument Valley, a scenic desert region straddling the Arizona-Utah border used in other John Ford movies. After seeing a preview screening of the film, 20th Century Fox studio boss Darryl F. Zanuck thought Ford's original cut was too long and had some weak spots, so he had Lloyd Bacon shoot new footage and heavily edit the film. Zanuck had Bacon cut 30 minutes from the film.

The final script of the movie varies considerably from historical fact to create additional dramatic conflict and character. Clementine Carter is not a historical person, and in this script, she appears to be an amalgam of Big Nose Kate and Josephine Earp. The Earps were also never cowboys, drovers, or cattle owners.

Matt Bailey, "If there is one film that deserves every word of praise ever uttered or written about it, it is John Ford's My Darling Clementine. Perhaps the greatest film in a career full of great films, arguably the finest achievement in a rich and magnificent genre, and undoubtedly the best version of one of America's most enduring myths, the film is an undeniable and genuine classic."

In the British Film Institute's 2012 Sight & Sound polls, seven critics and five directors named it one of their 10 favorite films. Roger Ebert included it in his list of The Great Movies, "one of the sweetest and most good-hearted of all Westerns". Director Sam Peckinpah considered this his favorite Western, and paid homage to it in several of his Westerns, including "Major Dundee" (1965) and "The Wild Bunch" (1969). The Japanese filmmaker Akira Kurosawa cited this as one of his 100 favorite films. Similarly, director Hayao Miyazaki called it one of his 10 favorite movies.