Children of Dune concludes the three-book story of Paul-Muad'Dib Atreides' life. His amazing young son, Leto II, helped by twin daughter Ghanima, surpasses Paul in finding the inner balance and unity of time and space required to lead humanity into a 4,000-year Golden Path of peace and prosperity. Paul's sister, Alia, exposed to the spice melange before birth, succumbs to the possession that she long fights, but which the twins channel adequately.

Stilgar feels responsible for Paul-Muad'Dib Atreides' 9-year-old twins who are discovering their father's powers within themselves. They prepare to launch a "Golden Path." Their Regent, Alia Atreides, is power-hungry and possessed by the evil Baron Harkonnen. On Salusa Secundus, Wensicia, daughter of the ousted Emperor, plots to murder the twins and put her son, Farad'n, on the throne. A blind "Preacher," whom many think is Paul, stirs up dissent in Arrakeen, visits Salusa, and turns over Duncan Idaho to the Corrinos. Paranoid and self-obsessed Alia fumes about conspiracy, missing that the twins are the targets. Arrakis moves towards civil war. Idaho appears to double cross Jessica, but reveals he works for The Preacher. Jessica agrees to tutor Farad'n.

Leto and Ghanima separate, with Jessica expecting him to fall into Sisterhood's hands and her to marry Farad'n. Jessica wonders if the Bene Gesserit is misusing her or about to discard her. Alia despairs just as she comes to believe that The Preacher is her brother. Idaho leaves Atreides service. Halleck and Namri capture Leto and force him to take the spice trips that he and Ghanima have avoided. Leto feels Time and Space and all of creation coalesce within him. Jessica begins Farad'n's training, but her mind is on Arrakis, where Alia and Irulan try to convince Ghanima to marry Farad'n. Leto is kept in a perpetual half-trance, which allows his inner thoughts to organize. He realizes the threat to spice posed by ecological change and goes to Shuloch, a smugglers' den, where he envisions "Kralizec," the "Typhoon Struggle," the inevitable end-day battle. He also begins his fearful physical transformation, putting on an impenetrable armor of sandtrout, which improve his agility and strength. Leto finds and confronts his father, who is indeed the blind Preacher.

Idaho escapes Alia's murder plot and goes to Tabr, where he and Alia's lover, Javid, die under circumstances that force an exodus, but Alia captures them. Leto's vast powers, which he widely demonstrates, spawn a new cult. Paul accepts his son's new universe and delivers one last sermon in Arrakeen on the day of his daughter's betrothal. Leto, Ghanima, Jessica, and Farad'n watch as Paul is assassinated and Alia leaps to her death. The novel concludes with Leto troubled by his lost humanity, but looking forward to a 4,000-year reign that will restore humanity to dignity and peace. Humankind will many times rise from its own ashes. Brother and sister will marry but since Leto is sterile, Farad'n will provide genetic material to a new House Atreides. Ghanima remarks that one of the twins has to accept agony, and Leto has always been the stronger.