Alcmaeon was born in Argos, the son of Amphiaraus, a celebrated seer of the Greek heroic age, and Eriphyle, the sister of Adrastus, king of Argos. Before Amphiaraus left for the doomed expedition of the Seven Against Thebes, he knew from his own prophecies that he would not return. The war had been forced upon him by a terrible compact: he and Adrastus had agreed that Eriphyle would decide any future dispute between them. Polynices, the exiled prince of Thebes, learned of this and bribed Eriphyle with the necklace of Harmonia. Eriphyle accepted the treasure and ruled that her husband must go to war. Amphiaraus obeyed, but before he rode out he charged his sons, Alcmaeon and Amphilochus, to avenge him by killing their mother and attacking Thebes.

The Seven fell at Thebes. Capaneus was struck by Zeus's thunderbolt while scaling the walls. The earth opened and swallowed Amphiaraus and his chariot. Polynices and his brother Eteocles killed each other in single combat. Only Adrastus escaped, carried away by his divine horse Arion. Ten years later, the sons of the fallen heroes, called the Epigoni, gathered for a second assault. An oracle promised victory if Alcmaeon led them. Eriphyle was bribed a second time, now by Thersander with the robe of Harmonia, and urged her sons to march. Alcmaeon led the Epigoni to victory and the capture of Thebes. In Apollodorus's account, after discovering his mother's second betrayal, he consulted Apollo about killing her; the god authorised the deed. He killed Eriphyle, either alone or with Amphilochus, depending on the account.

The vengeance brought no peace. Alcmaeon was pursued by the Erinyes and driven into madness for shedding his mother's blood. He wandered first to Arcadia, to his grandfather Oicles, and then to Psophis in the western Peloponnese. There King Phegeus purified him and gave him his daughter in marriage. Apollodorus calls her Arsinoe, while Pausanias names her Alphesiboea. Alcmaeon gave his bride the necklace and robe of Harmonia. But the fields of Psophis became barren, and the purification had not freed him from the consequences of the matricide. The treasures that had destroyed his parents had entered another household.

He turned again to Delphi. Pausanias explains the oracle's strange condition: he must find land which had not yet existed when he killed his mother. The new ground could not have witnessed the crime or been included in her curse. Alcmaeon eventually reached the mouth of the Achelous River in western Greece, where deposits carried downstream were creating fresh land. Apollodorus describes his arrival at the river's newly formed ground and his purification by Achelous, the river god. There he married Callirrhoe, a daughter of Achelous, and established a home. At the meeting of river and sea, the wanderer seemed to have found somewhere that could receive him.

But the treasures of Harmonia drew him back into danger. Callirrhoe wanted the famous necklace and robe, which Alcmaeon had left with his first wife at Psophis. He returned to Phegeus and claimed that he needed to dedicate them at Delphi to complete his release from madness. Phegeus believed him and handed them over. A servant then revealed that Alcmaeon intended to give them to Callirrhoe instead. Phegeus's sons ambushed and killed him. Apollodorus names the killers Pronous and Agenor, son of Phegeus; this Agenor is not the Phoenician king of the same name. Pausanias gives the alternative names Temenus and Axion. When Arsinoe condemned her brothers' deed in Apollodorus's version, they carried her to Tegea and falsely accused her of causing Alcmaeon's death.

Callirrhoe learned of her husband's murder and prayed to Zeus that her young sons might become adults at once and avenge their father. The god granted the prayer. Amphoterus and Acarnan grew suddenly into warriors, killed Phegeus's sons at the house of Agapenor in Tegea, and then went to Psophis, where they killed Phegeus and his wife. They carried the necklace and robe to Delphi and dedicated them there at Achelous's direction. Afterwards they gathered settlers and established themselves in Acarnania, the land associated with Acarnan's name. Pausanias also records a tomb of Alcmaeon at Psophis, shaded by cypresses which local people treated as sacred. The legend left traces both in the geography of western Greece and in the memory of the town where he died.