Nessus was born a centaur, one of the race of half-man half-horse creatures who sprang from the union of Ixion and the cloud-phantom Nephele on the slopes of Mount Pelion in Thessaly. His kind were wild and violent, famous for their inability to control their appetites for wine and women, and they had made themselves the enemies of civilised men from the moment of their creation. Nessus survived the great battle known as the Centauromachy, the war that broke out at the wedding of Pirithous, the king of the Lapiths, and Hippodamia, when the centaurs became drunk and tried to carry off the women of the wedding party. Most of the centaurs were killed in that battle, cut down by the swords of the Lapiths and the arrows of the hero Theseus, but Nessus escaped and made his way to the banks of the River Evenus in Aetolia, the region of western Greece between the Gulf of Corinth and the Ionian Sea. There he established himself as a ferryman, carrying travellers across the swift and treacherous waters for a fee, a centaur reduced to the labour of a beast of burden but still dangerous in his cunning.

The day that changed everything came when Heracles, the hero forced to complete twelve impossible labours as penance for a fit of madness in which he had killed his own wife and children, arrived at the Evenus with his new bride Deianira. Deianira was the daughter of Oeneus, the king of Calydon, a city in Aetolia famous for the great boar hunt that had drawn heroes from across Greece. Heracles had won her hand in marriage by defeating the river god Achelous, who had also sought to marry her, in a wrestling match so fierce that the god lost one of his horns. Now, travelling with his bride, Heracles came to the Evenus and found the river in flood, the winter rains having swollen it beyond its normal banks. The current was too strong for Deianira to swim, and Heracles, though he could have crossed alone, refused to leave her behind.

Nessus saw his opportunity. He approached the couple and offered to carry Deianira across the river on his back, a service for which he charged a fee. Heracles, who had fought centaurs before and knew their nature, was suspicious, but the river was impassable and Deianira was afraid of the water. He agreed, and Nessus lifted Deianira onto his equine back and waded into the current. Heracles, weighed down by his lion-skin and his quiver, swam across behind them, trusting that the centaur would not dare to betray him while he was still in sight. But Nessus had no intention of keeping his word. Midway across the river, with the water rushing around his hooves and Deianira clinging to his mane in terror, he turned and galloped for the far bank, intending to carry her off into the wilderness and claim her for himself. Deianira screamed, and Heracles, still in the water, heard her cry. He did not hesitate. He reached the bank, seized his bow, and nocked an arrow dipped in the poisonous blood of the Lernaean Hydra, the many-headed serpent he had slain as his second labour, whose venom was so deadly that a single drop could kill a man in agony. The arrow flew across the river and struck Nessus in the back, the barbed point emerging from his chest. The centaur staggered, his blood mixing with the river water, and collapsed on the far bank with Deianira still clinging to him.

What happened next was the work of a mind that knew it was dying and had nothing left to lose. Nessus, lying in his own blood with the Hydra's venom already burning through his veins, turned to Deianira and spoke with the voice of a man who has seen his death and chosen revenge over peace. He told her that his blood, now mingled with the poison of the Hydra, was a powerful love charm. If she ever feared that Heracles's love was waning, she need only anoint one of his shirts with the blood, and his heart would return to her with a passion greater than any he had ever felt. He urged her to collect the blood that dripped from his wound, to mix it with the seed that had fallen from him, and to keep it in a jar hidden from her husband. Deianira, young and trusting, believing that the dying centaur spoke the truth, did as he asked. She gathered the blood, stored it in a jar, and kept it secret for years, a love charm that she hoped she would never need but that she treasured as insurance against the day when Heracles's eye might wander.

Years passed. Heracles and Deianira lived together, and the jar of blood sat forgotten in a corner of their house. Then Heracles sacked the city of Oechalia, a kingdom in Euboea ruled by King Eurytus, and among the captives he brought back was Iole, the king's daughter, a woman of extraordinary beauty. Deianira saw the way Heracles looked at Iole, and she remembered the centaur's words. In despair, she took the jar of Nessus's blood, soaked one of Heracles's finest ceremonial shirts in it, and sent it to her husband through his attendant Lichas, a servant who had served the hero faithfully for years. She told Lichas that the shirt was a gift from her, a token of her love, and that Heracles should wear it during the sacrifice he was preparing to perform at Cape Cenaeum on the island of Euboea. Lichas, knowing nothing of the blood, delivered the shirt, and Heracles, pleased by his wife's gift, put it on.

The moment the shirt touched his skin and the heat of the sacrificial fire warmed it, the Hydra's venom, which had lain dormant in Nessus's blood for years, activated. It began to cook Heracles alive, eating through his flesh like acid, burning his skin and searing his bones. The hero who had strangled the Nemean Lion, who had slain the Hydra itself, who had held up the heavens for Atlas, was brought to his knees by a piece of cloth. He tore at the shirt, but it had fused to his body, and every movement only drove the poison deeper. In his agony, he seized Lichas, the innocent messenger who had brought the shirt, and hurled him into the sea, where the servant was transformed into a rock. Then Heracles, knowing that no mortal remedy could save him, made his way to Mount Oeta in Thessaly, the mountain where he had been born, and built a funeral pyre of oak and wild olive. He lay upon it, and his friend Philoctetes, a young man who would one day inherit the hero's bow and arrows, lit the fire. The flames consumed his mortal body, and from the pyre rose Heracles, no longer a man but a god, welcomed to Olympus by Athena and Zeus. Nessus's poison had done what no enemy, no monster, and no god had been able to do: it had ended the mortal life of the greatest hero Greece had ever known.

Deianira, when she learned what her jealousy and her trust in the centaur's words had done, killed herself in grief. Some said she hanged herself; others said she fell upon a sword. Either way, she died before the pyre on Mount Oeta had finished burning, the last victim of Nessus's dying curse. The centaur's body, left unburied on the banks of the Evenus, rotted where it fell, and the stench of his decay was so foul that the region around his corpse became known as Ozolian Locris, the "stinking" Locris, a name that clung to the land for centuries. In some traditions, the putrefied blood that seeped from his corpse into the ground created a spring of foul water, a permanent reminder of the centaur whose last act had been more terrible than any of his living crimes.