Jessica Atreides, a Bene Gesserit has a male child, contravening her instructions to produce a daughter. Nevertheless, the result, Paul, is the Kwisatz Haderach, the Bene Gesserit superman aimed for by the breeding programme. House Atreides gains control of Arrakis, a desert planet and source of the addictive spice Melange, but Harkonnen troops are there waiting to regain control. They take over using a traitor, Yueh, but Yueh gives Duke Leto a poison tooth to use to kill Baron Harkonnen. This fails. Paul and Jessica are kidnapped, but they escape with water-conserving stillsuits left by Yueh. They find the Fremen, fulfilling a Fremen prophecy in which Paul becomes their leader Muad' Dib. Paul leads them to overthrow the Harkonnens and stop Spice production. Jessica takes the Water of Life, turning her and her unborn child, Alia, into Reverend Mothers, with memory-lives of all their predecessors inside them. Paul takes the Water and gains the power to see into the future. The Emperor comes to Arrakis, but the Fremen overthrow him and Paul becomes the new Emperor by marrying his daughter. Later, with Paul as Emperor and Alia a goddess, a plot to kill him is devised. A ghola (clone) is made of Duncan Idaho, a friend of the old Duke, but he is programmed to kill Paul. The plotters set off a bomb which blinds Paul, but he can still see with his mind. Chani, his concubine, dies giving birth to twins. The ghola Duncan Idaho regains his old identity after overcoming his programming, and the plotters say they will do the same to Chani - if Paul relinquishes his throne. He refuses, but has now truly lost his sight, and gives himself up to the desert, as the Fremen law requires.

Later, Alia is the ruler as Jessica returns to Arrakis. The Preacher keeps causing a stir at the capital Arrakeen; many believe him to be Paul Muad'Dib. Ghanima and Leto II, Paul's children, embark on the "Golden Path" plan, to stop increasing water-richness from the killing off the sandworms, and therefore the spice. Alia becomes possessed with the memory-life of Baron Harkonnen. On Salusus Secondus, Farad'n is the new leader. Unknown to him, his mother has sent tigers to kill Leto and Ghanima. They escape, but, in accordance with the Golden Path, Ghanima hypnotises herself into believing that Leto was killed. She can remember the truth on hearing a catch phrase. She is captured by Alia, and Leto rides a worm to legendary Jacurutu, but he is captured by Gurney Halleck to be tested for abomination. Gurney also has orders to kill Leto, not from Jessica, as he believes, but from Alia. Idaho kidnaps Jessica and takes her to Farad'n. Farad'n displaces his mother, and Jessica teaches him the Bene Gesserit way, turning him into an Atreides. Leto escapes from his training, and, having taken the spice essence, is now prescient, like his father. In a spice trance, he covers himself with sand trout, which gives him superhuman strength and a living stillsuit, but it also changes his structure so he is no longer human, and will live 4000 years. Alia arranges a marriage between Farad'n and Ghanima, after which Ghanima will kill him. Leto finds the Preacher, who is revealed as Paul Muad'Dib, still alive. Duncan provokes Stilgar to kill him, so Stilgar, Ghanima and others flee into the desert. Alia sends men to find him and capture Ghanima. The Preacher is stabbed after condemning Alia. As Farad'n is ready to be wed, Leto and Ghanima (who has regained her memory) come in, and after Alia's abomination takes over, Leto kills her with his new powers. Leto is now Emperor, Farad'n (who gives the former his troops) is his scribe.

Much later, sand worms are becoming rare due to the increasing moisture engineered by Leto, who has mutated into a half-worm. He rules the universe and controls the spice with an iron hand. The daughter of his aide Moneo Atreides, Siona, leads a rebellion against him. The last of many gholas of Duncan Idaho attempts to kill him, but fails and is killed by Leto. The new ghola ordered by Leto has no memories since his original incarnation died. Nayla is a spy for Leto in Siona's group of rebels, whom Leto wants to mate with Duncan. Discovering that the last Duncan's assassination attempt was planned by the Ixian ambassador who supplied him, Leto replaces Duncan with Hwi Noree, a perfect woman created to seduce Leto and lead him to ruin. Face Dancers (who can change their appearance) launch an attack on the city. Leto marries Hwi, and Duncan, who also loves Hwi but can't have her because of Leto, rebels against him. The Bene Gesserit unsuccessfully attempt to kill Leto with spice essence. Leto takes Siona into the desert and gives her the spice essence so that she will become one of his "Fish Speaker" army and, like her father, understand Leto's Golden Path (which is simply the survival of the human race). However she still wants to kill him. Duncan, Siona and Nayla (whom Leto has made take a vow of obedience to Siona) plan to kill Leto as his royal cart passes over a bridge to his wedding. This succeeds. As he dies in the water, sand trout go out from his body to renew the spice cycle.

Much later, Dune (now known as Rakis) is desert again. The Bene Gesserit are raising another Duncan Idaho ghola on Gammu, after the others were assassinated by the Tleilaxu who made them. He has not regained him old memories yet, and has been changed in some unknown way by the Tleilaxu. Sheeana, a girl who can command sandworms, is taken by Rakian priests into their care. The Honoured Matres, who cultivate sexual powers (and who formed after the Scattering caused by Leto's Golden Path) are returning. Teg, a retired commander, is training the ghola. The Tleilaxu attack Sheeana and Duncan, but the former is rescued by the Bene Gesserit, and the latter, with Teg and Lucilla, escapes to an old Harkonnen no-chamber where he regains his memories.

Lucilla's task is to "imprint" Duncan sexually to control him, but he won't let her. Reverend Mother Odrade and Sheeana ride a worm to where Odrade discovers Leto's spice hoard with a message to the Bene Gesserit. Teg, the ghola and Lucilla are ambushed leaving the no-chamber, but all but Teg escape. Odrade forges an alliance between the Bene Gesserit and the Bene Tleilax. Teg's interrogation by Honoured Matres sends him into a trance, whereby he attains superhuman speed and semi-prescience, and escapes. Lucilla planned to meet up with Duncan on Gammu, but instead meets him after both of them are captured by Honoured Matres. Honoured Matre Murbella tries to imprint Duncan, but he imprints her too- this is what the Tleilaxu had secretly engineered in him, to use on Lucilla. He escapes. Teg is taken to Honoured Matre HQ, but kills them all in his state of super-speed. He gets a force of former colleagues to capture a no-ship to take a worm and Duncan to the Bene Gesserit planet of Chapter House. After they, Sheeana and Odrade (whom Teg predicted were coming by worm) leave, Rakis is destroyed by the Honoured Matres in an attempt to kill Duncan.

Later, a ghola of Teg is made by the Bene Gesserit, as Odrade (his daughter) is Mother Superior. Duncan and Murbella are sexually addicted to each other and must stay in the no-ship. Honoured Matres are taking over the universe, but Chapter House is yet undiscovered. It is being turned into a desert planet to house the sandworms. A new Scattering is planned to save the Bene Gesserit from extinction. The Honoured Matres have a secret weapon they can only use once. Lucilla is in their hands, but is eventually let off at Gammu, where she Shares with Rebecca, a Jewish Reverend Mother. Since a whole Bene Gesserit planet was destroyed by the Honoured Matres, only these two retain their memory lives. Lucilla is killed by Honoured Matres and Gammu is destroyed, but Rebecca hides in a no-shelter underground. Odrade decides to talk with the Honoured Matres at Junction about a surrender, while in reality attacking them after a feint at Gammu. The Teg ghola regains his memories after imprintation by Sheeana, and Murbella becomes a Reverend Mother. She, Sheeana, Odrade and others Share for fear of death while on the Gammu feint/Junction attack, for which purpose they are dropped off at Junction. Rebecca is rescued from Gammu as it is attacked, thus saving the lost memory-lives. The Honoured Matre weapon is used as Junction is attacked, killing many, but Murbella kills the Great Honoured Matre, assuming that position herself, and also assuming the position of Mother Superior after Odrade dies. She takes the Honoured Matre Supreme Council to Chapter House to re-educate them in Bene Gesserit ways as she was, and to integrate the two factions. As some Bene Gesserit don't like this, they, Duncan, Sheeana and Teg lift off in the no-ship to begin a new life.