In the distant future, Duke Leto of House Atreides, ruler of the ocean planet Caladan, is assigned by the Padishah Emperor Shaddam IV of House Corrino to replace House Harkonnen as the fiefholder of Arrakis, a harsh desert planet and the only source of "spice", a valuable psychotropic drug that imparts heightened vitality and awareness to its users. It is critical for faster-than-light interstellar travel, as it grants Spacing Guild Navigators the limited prescience needed for safe navigation. Shaddam intends to have House Harkonnen retake the planet with the secret aid of his Sardaukar troops, eradicating House Atreides, whose spreading influence he considers a threat to his power. Leto is reluctant, but sees the advantages of controlling Arrakis and forming an alliance with its native population, skilled fighters known as the Fremen.

Leto's concubine, Lady Jessica, is an acolyte of the Bene Gesserit, an exclusive sisterhood whose members possess advanced physical and mental abilities. As part of their centuries-long breeding program, they instructed her to bear a daughter whose son would become the Kwisatz Haderach, a Bene Gesserit and messianic superbeing with the clairvoyance necessary to guide humanity to a better future. However, she disobeyed and bore a son, Paul. Throughout his life he is trained by Leto's aides, Duncan Idaho, Gurney Halleck, Suk doctor Wellington Yueh, and the Mentat Thufir Hawat, while Jessica teaches him Bene Gesserit disciplines. Paul confides in Jessica and Duncan that he is troubled by visions of the future. In response, the Reverend Mother and Imperial Truthsayer Gaius Helen Mohiam visits Caladan and subjects him to a death-alternative test to assess his humanity and impulse control, which he passes. Mohiam insists that Baron Vladimir Harkonnen spare Paul and Jessica during his coup, to which he duplicitously agrees.

House Atreides arrives at Arrakeen, the fortress stronghold on Arrakis, where Duncan's advance party learned about the planet and Fremen. The natives revere Paul and Jessica, which Jessica explains is due to the Bene Gesserit sowing beliefs on the planet centuries earlier. Leto negotiates with the Fremen's chieftain, Stilgar, and meets planetologist and Imperial Judge of the Change Dr. Liet-Kynes, known outside the Fremen as Dr. Kynes. Kynes informs Leto, Paul, and Halleck of the dangers of spice harvesting, including giant sandworms which travel under the desert. During a flight, they spot a sandworm approaching a spice harvester with a stranded crew, whom they successfully rescue. However, Paul's exposure to the spice outside triggers intense premonitions.