During his long reign, Leto has enforced a state of peace throughout his multigalactic empire, both through tight control of his enormous hoard of the spice melange and the military might of his Fish Speaker army. The old Imperium is basically non-existent; the Landsraad has ceased to exist and only a few remnants of the Great Houses survive. The Bene Gesserit and Spacing Guild have endured, although both have been forced to adapt to Leto's absolute control over melange and his powerful prescience, and CHOAM has been reduced to a shadow of its former self. His reign is considered by many to be depraved and despotic, but he is confident that his actions will ensure the survival of the human race.
Leto has employed a series of gholas grown from the cells of Duncan Idaho, the faithful Sword Master of House Atreides. Duncan functions both as the captain of Leto's guard and as a familiar face to calm Leto in his moments of distress. They remind Leto of his family, and he feels that he owes Duncan for his service and devotion to House Atreides. Over the centuries, a significant number of the gholas have attempted to assassinate Leto through various means after struggling with the conflict between their intense loyalty to House Atreides and the moral disgust triggered by the repression and stagnation Leto has forced upon the Empire. These feelings, compounded with the uneasy doubt caused by being millennia out of their time, drives some of the Duncan Idaho gholas insane.
Leto's "Golden Path," as he calls it, is a millennia-spanning attempt to produce a human who is invisible to a watcher gifted with prescience. This breeding plan, begun with the marriage of Leto's twin sister Ghanima to Farad'n Corrino, has resulted in Leto's majordomo Moneo Atreides and his daughter Siona. Moneo has served Leto faithfully for the majority of his life, having been a rebel until he was shown the Golden Path in a test by Leto. Siona is the leader of a group of rebels seeking to overthrow the God Emperor and locate his hidden hoard of melange. Unbeknownst to Siona, Nayla — her close friend and de facto bodyguard — worships Leto, and is under orders to protect and obey Siona in all things while reporting of her rebellious activities.
During a raid on his Citadel, Siona and her friends steal, among other things, a series of excerpts from Leto's private journal. Unknown to them, Leto is aware of their activities and allows them to continue. In perusing some of the items and documents stolen from the Citadel, Siona learns that Leto remains capable of love, and plots to use this as a weapon against him. At the same time, the new Ixian ambassador, Hwi Noree, is sent to the court of the God Emperor. Immediately entranced by her beauty, grace, and purity, Leto begins to be tortured by the knowledge that he and Hwi are separated by his continued transformation. For her part, Hwi desires nothing more than to serve the God Emperor, and she quickly becomes a confidante, finally expressing her love of Leto. The latest incarnation of Duncan is also captivated by Hwi's beauty, but is rebuffed by Leto, who warns that Hwi is his alone.
Because of his intense feelings for Hwi and the fact that she had never appeared in his prescient visions, Leto realizes that she is a trap, trained and sent by the Ixians to weaken him. However, he is unable to send her away, and she gladly accepts his offer to remain. It is revealed that Hwi had been grown inside an Ixian no-globe — a device that shields its occupants from prescient view — from cells of a former Ixian ambassador, Malky, who had been a cynical and roguish friend of the God Emperor.
Through discussions with Moneo and Leto, Duncan learns about Leto's transformation, the Fish Speakers, and the oppressive measures Leto takes to maintain his absolute control over the Empire. He begins to grow more agitated and restless, though he continues in his duties, defending the God Emperor from an attack by Tleilaxu Face Dancers. Duncan struggles with feelings of inadequacy and the confusion and disorientation that result from existing in a time alien to him. Duncan meets Siona, and though the two of them are coldly formal to one another, they eventually unite to kill Leto and end his tyrannical rule over mankind.
Leto and Hwi decide to marry, and lead a wedding procession from Leto's Little Citadel to Tuono Village, where Duncan and Siona have been sent. While crossing the Idaho River, Siona orders Nayla to cut the supports of the bridge with a lasgun, spilling Moneo, Hwi, Leto, and a number of couriers into the jagged rocks in the canyon below. Leto survives the fall, but is immersed in water, and his body begins to dissolve, just as the sandworms of ancient Dune. In a final conversation with Siona and Duncan, Leto reveals that Siona is the embodiment of the Golden Path, a human completely shielded from prescient view. He explains that humanity is now free from the domination of oracles, free to scatter throughout the universe, never again to face complete domination. After revealing the location of his secret spice hoard, Leto dies, leaving Duncan and Siona to face the task of managing the empire.