Twelve years after the events described in Dune (1965), Paul "Muad'Dib" Atreides rules as Emperor, following a jihad which conquered most of the human universe. Paul unleashed this jihad by accepting the role of messiah to the Fremen. 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 sixty-one 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, the Bene Gesserit Reverend Mother Gaius Helen Mohiam enlisting Paul's own consort Princess Irulan, daughter of the deposed Padishah Emperor Shaddam Corrino 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, but has foreseen that the birth of his heir will bring Chani's death, and does not want to lose her. With the Guild Navigator Edric shielding the conspiracy from Paul's prescience, the Tleilaxu Face Dancer Scytale gives Paul a gift he cannot resist: a Tleilaxu-grown ghola of 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; she is soon pregnant.
Otheym, one of Paul's former Fedaykin death commandos, reveals evidence of a Fremen conspiracy against Paul. Otheym gives Paul his little 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 is able to continue in leadership by fixing his actions precisely in line with what his previous oracular visions showed him; by moving through his life in lockstep with his previous 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 so long as he wishes to appear sighted. 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.
Hayt interrogates Bijaz, but the little man — secretly an agent of the Tleilaxu — uses a specific humming intonation that renders Hayt open to implanted commands. Bijaz programs Hayt 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. Unknown to Hayt, this also activates a hidden compulsion that will force him to kill Paul, given the appropriate circumstances. News is brought that Chani has died giving birth to two healthy children; like Paul's sister Alia, they are "pre-born" — born fully conscious with Kwisatz Haderach-like access to ancestral memories, in their case because of in utero exposure to the spice. News of the birth is delivered to Paul and his reaction to it triggers the compulsions in the mind of Hayt, who attempts to kill Paul. Reacting against its own programming owing to the trauma of the attempt, Hayt's body remembers itself, and a new consciousness arises that is a mix of Duncan Idaho and Hayt, unconditioned by the Tleilaxu programming. Because Paul had foreseen the birth of only a daughter (and not twins), his prophetic visions fail, rendering him totally blind. As he nears a crucial decision point, he is thrust into a deadly standoff: Scytale holds a knife to the necks of Paul's children. The ability to restore a ghola's memory proven, Scytale offers to revive Chani as a ghola in return for Paul's abdication. Paul receives a prescient vision from the perspective of his newborn son Leto, and is able to throw a dagger and kill Scytale.
With Paul's visions gone, he is now blind, and he chooses to walk into the desert in the Fremen tradition, 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.