Nine years after Emperor Paul Muad'Dib walked into the desert, blind, the ecological transformation of Dune has reached the point where some Fremen are living without stillsuits in the less arid climate and have started to move out of the sietches and into the villages and cities. As the old ways erode, more and more pilgrims arrive to experience the planet of Muad'Dib. The Imperial high council has lost its political might and is powerless to control the Jihad.
Paul's young twin children, Leto II and Ghanima, have concluded that their guardian Alia has succumbed to abomination— the possession by one of her ancestors — and fear that a similar fate awaits them. They (and Alia) also realize that the terraforming of Dune will kill all the sandworms, thus destroying the source of the spice, but the thing which has possessed Alia desires this outcome. Leto also fears that,like his father, he will be trapped by his prescience.
Possessed by the persona of her grandfather Baron Vladimir Harkonnen, Alia fears that her mother Lady Jessica, about to return to Arrakis, will recognize her abomination. Meanwhile, a new religious figure called "The Preacher" has risen in the desert, railing against the religious government's injustices and the changes among the Fremen. Some Fremen believe he is Paul Atreides. Princess Wensicia of the fallen House Corrino on Salusa Secundus plots to assassinate the twins and regain power.
Jessica returns to Arrakis and recognizes that her daughter has been possessed, but finds no signs of abomination in the twins. Leto arranges for Fremen leader Stilgar to protect his sister if there is an attempt on their lives. The Preacher journeys to Salusa Secundus to meet Wensicia's son Farad'n, and in return pledges Duncan Idaho as an agent of House Corrino. Alia attempts to assassinate Jessica, who escapes into the desert with Duncan's help, precipitating a rebellion among the Fremen. The twins anticipate and survive the Corrino assassination plot. Leto leaves to seek out the Preacher while Ghanima, masking her memory with self-hypnosis, reports falsely that her brother had been murdered. Duncan and Jessica flee to Salusa Secundus where Jessica begins to mentor the Corrino heir. He seizes power from his regent mother Wensicia and allies with the Bene Gesserit, who promise to marry him to Ghanima and support his bid for coronation as Emperor.
A band of Fremen outlaws capture Leto and force him to undergo the spice trance at the suggestion of Gurney, who has infiltrated the group on Jessica's orders. His spice-induced visions show him a myriad of possible futures where humanity has become extinct and only one where humanity survives. He names this future "The Golden Path" and resolves to bring it to fruition. He escapes his captors and sacrifices his humanity in pursuit of the Golden Path by physically fusing with a school of sandtrout, gaining superhuman strength and near-invulnerability. He travels across the desert and confronts the Preacher who does, in fact, prove to be his father Paul.
Duncan returns to Arrakis and provokes Stilgar into killing him. With Stilgar's neutrality now untenable, he seizes Ghanima and flees. Alia recaptures Ghanima and arranges her marriage to Farad'n, planning to exploit the expected chaos when Ghanima kills him to avenge her brother's murder. The Preacher and Leto return to the capital to confront Alia, who has the Preacher murdered, revealing his true identity. Leto reveals himself in a display of superhuman strength and triggers the return of Ghanima's genuine memories. He confronts Alia and offers to help her overcome her possession, but she is overwhelmed by her ancestral personae and elects to commit suicide.
Leto declares himself Emperor and asserts control over the Fremen. Farad'n enlists in his service and delivers control of the Corrino armies. The seemingly immortal and omnipotent Leto is left as Emperor of the Known Universe, with Ghanima at his side. Leto will wed his own sister, but Farad'n, now renamed Harq al Ada ( The Breaking of the Way ), will become Ghanima's consort and continue the Atreides line.