In a desolate Western ghost town during the American Civil War, Mexican bandit Tuco Ramirez ("The Ugly") narrowly escapes three bounty hunters, killing two and wounding a third, Elam.
The Man with No Name—"Monco"/"Manco"— and Colonel Douglas Mortimer—the "Man in Black"—are two bounty hunters in pursuit of "El Indio," one of the most wanted fugitives in the Wild West, and his gang. El Indio is ruthless, clever, and brutal. He has a musical pocketwatch that he plays before engaging in gun duels: "When the chimes finish, begin," he says. Flashbacks reveal that El Indio took the watch from a young woman whom El Indio found with her lover (in Joe Millard's novelization of the film, her newly wed husband), killed him, and raped her; she killed herself while being raped. There is a photograph of the woman inside the cover of the watch; it was a gift from her lover (in the novelization, it was a wedding gift from her brother).
In Texas 1858, the Speck brothers, Ace and Dicky, drive black slaves on foot. Among the shackled slaves is Django, sold off and separated from his wife, Broomhilda von Shaft. The Speck brothers are stopped by Dr. King Schultz, a German ex-dentist and bounty hunter from Düsseldorf, Prussia. Schultz asks to buy one of the slaves; when he questions Django about his knowledge of the Brittle brothers, for whom Schultz is carrying a warrant, Ace becomes irritated and aims his shotgun at Schultz. Schultz quickly kills Ace and leaves Dicky at the mercy of the newly freed slaves, who shoot Dicky in the head.
A stranger arrives at the little Mexican border town of San Miguel. Silvanito, the town's innkeeper, tells the Stranger about a feud between two families vying to gain control of the town: on the one side, the Rojo brothers: Don Miguel, Esteban and Ramón; on the other, the family of the town sheriff, John Baxter. The Stranger decides to play each family against the other in order to make money, and proves his speed and accuracy with his gun to both sides by shooting the four men who teased him as he entered town with ease.
Henry Pollicut, a corrupt Utahn banker, has Gordon, a man with evidence against him, and his wife murdered by two bounty killers. Fearing that Gordon's son will give them away, one of the killers slices his throat, rendering him permanently mute. Years later, the son, armed with a Mauser C96, extracts his revenge by assassinating the bounty killer and shooting Pollicut’s right-hand thumb.
Jack Beauregard (Henry Fonda) is an aging legendary gunslinger who wants to retire in peace in Europe to get away from young gunmen constantly trying to test themselves against the master. The film opens with three gunmen attempting to ambush Beauregard in a barbershop. After Beauregard has dispatched them, the barber's son asks his father if there is anyone in the world faster than Beauregard, to which the barber replies "Faster than him? Nobody!"
Django is a drifter who drags a closed coffin around with him. He rescues a young woman, María, who is about to be murdered by bandits led by Major Jackson (Eduardo Fajardo), the man whom Django is seeking and wants to kill in revenge for him for killing his wife. After killing most of Jackson's men, Django makes a deal with a Mexican bandit general, Hugo Rodriguez, who is in conflict with Jackson, and the two steal a large quantity of gold from a Mexican Army fort (where Jackson is doing business with a government general). When Rodriguez refuses to give Django his share of the haul, Django and Maria steal the gold. Unfortunately, the gold falls into quicksand. When Rodriguez catches up to them, María is shot (though she survives) and Django's hands are crushed by Rodriguez's men as punishment for being a thief. When the bandits return to Mexico, Rodríguez and his men are massacred by Jackson and the Mexican Army. After killing Nathaniel, Jackson goes looking for Django in a cemetery. However, Django, who has bitten off the trigger-guard of his pistol, kills Jackson and his five surviving men by pressing the trigger of his gun against the cross of the grave of a female acquaintance of Django's whom Jackson had killed and repeatedly dropping the hammer.
Scott, fils d'une prostituée, est le souffre douleur de la petite ville tranquille de Clifton. Un jour, le pistolero Talby débarque et, en prenant la défense du jeune homme, tue un homme. Il est relâché pour légitime défense et prend sous son aile Scott, qui s'avère être un excellent tireur. Le maître et l'élève décident de se venger des notables de Clifton et prennent peu à peu le contrôle de la ville avant de s'opposer...
Paco Roman (Musante), a Mexican peasant, rebels against his rich boss and humiliates him. He is later captured, but saved from a certain death by his friends. Meanwhile, Sergei Kowalski (Nero), a Polish mercenary, arrives in Mexico and makes a deal with two Garcia brothers to take their silver safely across the border. Curly (Palance) sees the three men talking and tracks down the brothers to find out what they hired Kowalski for, after which Curly kills the two.
Professor Brad Fletcher (Volontè), a teacher from New England, leaves his job and travels to Texas due to his ill health. After arriving in the west, he ends up taken hostage by a wounded outlaw, Solomon "Beauregard" Bennet (Milian). Fletcher helps Bennet regain his health and manages to convince Bennet that he is more valuable to him alive than dead. Through their uneasy friendship, Fletcher takes an interest in the outlaw way of life. Instead of returning home, he decides to join the "Bennet's Raiders".
Bill (John Phillip Law), a boy whose father was killed and mother and sister were raped and murdered in front of him by a gang, sets out 15 years later to exact revenge, having used the time to become an expert marksman with a gun.
After the U.S. Civil War, Keoma (Nero), part Indian and part white, returns to his home town to find his half-brothers in alliance with a petty tyrant named Caldwell. Caldwell and his gang rule over the town with an iron fist. With the help of his father and George, an old Black friend, he vows revenge. Keoma also shows compassion when he saves a pregnant woman from a group sent by Caldwell's group to be quarantined in a mine camp full of plague victims. Keoma is constantly visited by the apparition of an older woman ("The Witch") who saved him during the massacre of an Indian camp.
The two Mexican brothers Chuncho and Santo and their mutual US-American friend Bill support the revolution in Mexico by delivering stolen guns to a rebel leader. Their mutual contempt for the current government unites the three men, but Chuncho only strives for maximum profit, whereas Santo is driven by political idealism. In the course of action their motives
Colonel Jonas is a fanatical and unrepentant Confederate who led a regiment called the Hellbenders in the recently ended Civil War. Similar to Edmond O'Brien's character in Rio Conchos, he is determined to reorganise the Southern Army and defeat the Union. With his sons Ben, greedy Nat, and rapist Jeff, he massacres Union soldiers transporting a consignment of banknotes and conceals the loot in a coffin supposedly belonging to a deceased Confederate officer, Captain Ambrose who was killed in the Battle of Nashville.
Sabata, a man of few words, arrives in a small Texas town to foil a bank robbery, and discovers that it was a plot by the town's leaders, who want to sell the town to the railroad. Sabata blackmails the leader, Stengel, who then sends various thugs to try and kill him, among them a conflicted killer named Banjo, so named for the musical instrument he carries that conceals a rifle.