In a prologue filled with genealogical detail, Amphitryon outlines the ancestral history of Herakles' and Lycus' families. Lycus is ruling Thebes unlawfully and is about to kill Amphitryon, and—because Megara is the daughter of the lawful king Creon—Herakles' wife Megara and their children. Herakles cannot help his family, for he is in Hades engaged in the last of his twelve labours: bringing back the monster Cerberus who guards the gates there. The family has taken refuge at the altar of Zeus; they are forbidden to enter their palace and are watched too closely to escape.
The Chorus sympathize with them and encourage them, but, being old men, are unable to help. Lycus comes to ask how long they are going to try to prolong their lives by clinging to the altar. He claims that Herakles has been killed in Hades and will never help them. He justifies the proposed slaughter, claiming that Herakles' children will attempt to avenge their grandfather, Creon, by killing Lycus when they grow up. He depreciates the deeds of Herakles, calling him a coward for using a bow instead of a spear. Amphitryon, point by point, argues the other side and asks permission for them to go into exile. Lycus declares that he is through with words and orders his men to bring logs, stack them around the altar, and burn the suppliants alive.
Megara refuses to be burned alive: that is a coward's death. She has given up hope for Herakles' return and gets permission from Lycus to dress the children in robes of death to face their executioners. The old men of the Chorus have stoutly defended Herakles' family, but, because of their age, can do little more than disagree with Lycus and sing in praise of Herakles' famous labours.
Megara returns with the children, dressed for death. She tells of the kingdoms Herakles had planned to give each of them and of the brides she intended them to marry. As Amphitryon laments the futility of the life he has lived, Megara catches sight of Herakles approaching. When Herakles hears the story of Creon's overthrow and Lycus' plan to kill Megara and the children, he resolves upon revenge. He tells them the reason for his long absence is that in addition to bringing Cerberus back from Hades and imprisoning him, he also brought back Theseus, who is now on his way to his home in Athens. With the children clinging to his robes, he goes into the palace with Megara.
Lycus returns and, impatient at finding only Amphitryon ready, storms into the palace to get the others. He is met inside by Herakles, and killed. The Chorus sing a joyful song of celebration, but it is interrupted by the appearance of Iris and Madness, hovering over the house.
Iris announces that she has come to make Herakles kill his own children by driving him mad. Hera, Zeus' wife, is behind the plan: she has hated Herakles since birth because Zeus was his father. She also resents his god-like strength and wants to humble him.
A Messenger reports that when the fit of madness fell on Herakles, he believed he had to kill Eurystheus, the king who assigned his labours. Moving from room to room, he fancied that he was going from country to country. When Amphitryon tried to stop him, he thought it was Eurystheus, and his own children those of Eurystheus. In his madness he killed his three sons and his wife. When he threatened Amphitryon, Athena struck him and he fell asleep. The palace doors are opened to reveal Herakles, now asleep and tied to a pillar, surrounded by the bodies of his wife and children. When he wakes up, Amphitryon tells him what he has done; in his shame he wants to commit suicide.
Theseus, king of Athens, whom Herakles had freed from Hades, arrives; he has heard that Lycus had overthrown Creon and desires to help overthrow Lycus. When he hears what Herakles has done, he asks him to uncover his head. Friendship, Theseus says, is greater than any fear he has of pollution from someone guilty of kindred bloodshed. Herakles, not easily comforted, says he can be welcome to no man; it would be better for him to commit suicide. Theseus offers him hospitality in Athens and half his wealth. He argues that even the gods commit evil acts, such as forbidden marriages, yet continue to live on Olympus and face out their crimes. Why shouldn't Herakles? Herakles vehemently denies this line of argument: such stories of the gods, he says, are merely the inventions of poets. A deity, if really such, can have no desires. Finally convinced that it would be cowardly to commit suicide, he resolves to go to Athens with Theseus. The law forbids him to remain in Thebes or even attend the funeral of his wife and children. He asks his father to bury his dead, and, leaning on Theseus, leaves.