Deianira was born in Calydon, a city in Aetolia in western Greece, the daughter of King Oeneus and his queen Althaea. Her father was a descendant of the wine-god Dionysus, and her mother was a granddaughter of Ares, the god of war. Her brother was Meleager, the hero who led the great hunt of the Calydonian Boar, a monstrous creature sent by Artemis, the goddess of the hunt, to punish Oeneus for forgetting her in his harvest sacrifices. Meleager killed the boar but died in the quarrel that followed, killed by his own mother in revenge for the death of her brothers. Deianira grew up in a house shadowed by divine punishment and family bloodshed, and she learned early that the gods did not forgive mortal forgetfulness.

When Deianira came of age, she attracted two suitors of very different kinds. One was Heracles, the son of Zeus and the mortal woman Alcmene, the hero whose strength was legendary across Greece and whose labours had taken him from the underworld to the garden of the Hesperides. The other was Achelous, the river-god whose waters flowed through Aetolia and who could transform his shape at will, becoming now a bull, now a serpent, now a man with the horns of a bull. Heracles and Achelous fought for her hand in a wrestling match beside the river, and the hero broke off one of the river-god's horns, which became the cornucopia, the horn of plenty that symbolises abundance. Defeated, Achelous withdrew, and Deianira became the wife of Heracles, the last and most famous of his many marriages.

The marriage was happy but brief. Heracles could not stay in one place, and his labours and his temper kept him wandering. During one of his journeys, he and Deianira came to the river Evenus, where the centaur Nessus, a creature half-man and half-horse, offered to carry Deianira across the river while Heracles swam. Heracles agreed, but when he reached the far bank, he looked back to see Nessus attempting to rape his wife. The hero drew one of his arrows, tipped with the venomous blood of the Hydra, the many-headed serpent he had slain as his second labour, and shot the centaur through the heart. As Nessus lay dying, he called Deianira to him and whispered a secret: his blood, mixed with the semen that stained his wound, was a powerful love charm. If Heracles ever looked at another woman, Deianira need only dip a shirt in the centaur's blood and give it to her husband to wear, and his heart would return to her alone. Deianira, young and fearful of losing the greatest hero in Greece, collected the blood in a jar and kept it hidden, hoping she would never need to use it.

Years passed. Heracles campaigned against the king of Oechalia, a city in Euboea, and when he sacked the city, he took the king's daughter Iole as a captive and a concubine. He sent a messenger ahead to Trachis, where Deianira waited with their children, instructing her to prepare a fine robe for him to wear during the victory sacrifice he planned to offer to Zeus. Deianira, hearing that Iole was young and beautiful and that Heracles had fallen in love with her, remembered the centaur's promise. She took the finest shirt she owned, dipped it in Nessus's blood, and sent it to her husband with the messenger, believing that the love charm would restore his devotion and drive Iole from his mind.

The shirt was a death sentence. When Heracles put it on and the warmth of his body heated the fabric, the Hydra's venom, dormant in the centaur's blood, awoke and began to eat through his skin. The pain was beyond anything the hero had ever endured, greater than the Nemean Lion's claws, greater than the Hydra's fangs, greater than the torment of his enslavement to Queen Omphale. He tore the shirt from his body, but pieces of it clung to his flesh, and the poison spread with every movement. He was carried to Mount Oeta, the great mountain that rises above Trachis, and there he commanded his son Hyllus, the eldest of his children by Deianira, to build a funeral pyre and place him upon it. Heracles climbed the pyre and lay down, and Philoctetes, a young companion, lit the flames. The hero's mortal body burned away, and his divine soul ascended to Olympus, where he was welcomed among the gods as one of their own.

When Deianira learned what she had done, she was consumed with grief and guilt. She had not meant to kill him. She had only wanted him to love her. She took her own life, either by hanging herself or by falling upon a sword, and her body was buried beside the road to Mount Oeta, where travellers could see her tomb and remember the woman who destroyed the man she loved. The messenger who had carried the shirt to Heracles, a man named Lichas, had also died, thrown by the enraged hero from the cliffs of Mount Oeta into the sea below, his body shattered on the rocks.