Twelve years after the events described in Dune (1965), Paul "Muad'Dib" Atreides rules as Emperor. By accepting the role of messiah to the Fremen, Paul had unleashed a jihad which conquered most of the known universe. While Paul is the most powerful emperor ever known, he is powerless to stop the lethal excesses of the religious juggernaut he has created. Although 61 billion people have perished, Paul's prescient visions indicate that this is far from the worst possible outcome for humanity. Motivated by this knowledge, Paul hopes to set humanity on a course that will not inevitably lead to stagnation and destruction, while at the same time acting as ruler of the empire and focal point of the Fremen religion.
The Bene Gesserit, Spacing Guild, and Tleilaxu enter into a conspiracy to dethrone Paul, and the Bene Gesserit Reverend Mother Gaius Helen Mohiam enlists Paul's own consort Princess Irulan, daughter of the deposed Padishah Emperor Shaddam IV. Paul has refused to father a child with Irulan (or even touch her), but his Fremen concubine Chani has also failed to produce an heir, causing tension within his monarchy. Desperate both to secure her place in the Atreides dynasty and to preserve the Atreides bloodline for the Bene Gesserit breeding program, Irulan has secretly been giving contraceptives to Chani. Paul is aware of this fact, but has foreseen that the birth of his heir will bring Chani's death, and does not want to lose her. He sees this in a terrifying vision of a moon that falls from the sky of Dune. Because of the way oracles interfere with one another's prescience, the Guild Navigator Edric is able to shield the conspiracy from Paul's visions of the future. The Tleilaxu Face Dancer Scytale gives Paul a gift he cannot resist: a Tleilaxu-grown ghola of the deceased Duncan Idaho, Paul's childhood teacher and friend, now called "Hayt". The conspirators hope the presence of Hayt will undermine Paul's ability to rule by forcing Paul to question himself and the empire he has created. Furthermore, Paul's acceptance of the gift weakens his support among the Fremen, who see the Tleilaxu and their tools as unclean. Chani, taking matters into her own hands, switches to a traditional Fremen fertility diet, preventing Irulan from being able to tamper with her food, and soon becomes pregnant.
Otheym, one of Paul's former Fedaykin death commandos, reveals evidence of a Fremen conspiracy against Paul. Otheym gives Paul his dwarf Tleilaxu servant Bijaz, who like a recording machine, can remember faces, names, and details. Paul accepts reluctantly, seeing the strands of a Tleilaxu plot. As Paul's soldiers attack the conspirators, others set off an atomic weapon called a stone burner, purchased from the Tleilaxu, that destroys the area and blinds Paul. By tradition, all blind Fremen are abandoned in the desert, but Paul shocks the Fremen and entrenches his godhood by proving he can still see, even without eyes. His oracular powers have become so developed that he can foresee in his mind everything that happens, as though his eyes still function. By moving through his life in lockstep with his visions, he can see even the slightest details of the world around him. The disadvantage of this is his inability to change any part of his destiny, trapping him in a hellish boredom. The unraveling of the Fremen conspiracy reveals that Korba, a former Fedaykin and now high priest of Paul's church, is among Paul's enemies.
Duncan interrogates Bijaz, but the little man—actually an agent of the Tleilaxu—uses a specific humming intonation that renders Duncan open to implanted commands. Bijaz programs Duncan to offer Paul a bargain when Chani dies: Chani's rebirth as a ghola, and the hope that Duncan Idaho's memories might be reawakened, in return for Paul sacrificing the throne and going into exile. Bijaz also implants a compulsion that will force Duncan to attempt to kill Paul, given the appropriate circumstances. Duncan remains oblivious of the programming. Eventually, news is brought that Chani has died giving birth. The grief of his loss is the falling moon that he foresaw in an earlier vision, and Paul stumbles, truly blind now, having removed himself from the prison of his own precise vision. Paul's reaction to his wife's death triggers the compulsions in the mind of Duncan, who attempts to kill Paul. Rather than kill his beloved Paul, though,Duncan's ghola body reacts against its own programming and recovers Duncan's full consciousness. He remains conscious of the Zen-Sunni and Mentat training given to Duncan by the Tleilaxu, but is no longer bound to their programming.
Paul and Chani's newborn twins are "pre-born", like Paul's sister Alia had been, and come into the world fully conscious with Kwisatz Haderach-like access to ancestral memories thanks to a combination of their genes and an in utero exposure to the quantities of spice in Chani's special pregnancy diet. Scytale offers to revive Chani as a ghola in return for all of Paul's CHOAM holdings. Paul refuses to submit to the possibility that the Tleilaxu might program Chani in some diabolical way, and Scytale threatens the infants with a knife while he negotiates with Alia. By successfully escaping the oracular trap and setting the universe on a new path, Paul has been rendered completely blind, yet he is able to kill Scytale with an accurately aimed dagger due to a vision from his son's perspective.
Now prophetically and physically blind, Paul chooses to embrace the Fremen tradition of a blind man walking alone into the desert, winning the fealty of the Fremen for his children, who will inherit his mantle of emperor. Paul leaves Alia, now romantically involved with Duncan, as regent for the twins, whom he has named Leto and Ghanima. Duncan notes the irony that Paul and Chani's deaths had enabled them to triumph against their enemies, and that Paul has escaped deification by walking into the desert as a man, while guaranteeing Fremen support for the Atreides line.