In the mid-16th century, a Spanish expedition led by conquistador Gonzalo Pizarro sets out from the Andes Mountains down into the Amazon basin in search of the mythical city of gold, El Dorado. Accompanying Pizarro is a diverse group of soldiers, Indian slaves, and Don Pedro de Ursua, who is in command of a smaller, advance detachment on a raft. The hostile environment soon challenges the party's progress, as they struggle with the dense jungle, treacherous rapids, and the growing sense of desperation. Tensions escalate as the perilous journey pushes the men to their physical and psychological limits.

As the conditions worsen and morale plummets, one of the soldiers, Lope de Aguirre, becomes increasingly power-hungry and disillusioned with the leadership. Aguirre assumes control of the increasingly mutinous detachment through a combination of manipulation and force, casting a vision of grandeur and defiance against the Spanish crown. His grip on reality loosens amid dreams of conquest and glory, leading his followers further into the precarious depths of the Amazon and into the realm of madness, with his own daughter Inez and the noblewoman Floresca caught up in his delusional quest. The journey becomes a harrowing descent into the darkness of the human spirit, as Aguirre's lust for power leads to a brutal struggle for survival.