An extremely contagious and lethal strain of influenza is developed as a biological weapon in a secret U.S. Department of Defense laboratory. It is described as being 99.4% fatal. The Complete and Uncut Edition includes a prologue detailing the development of the virus and the security breach that causes its accidental release. Nearly all the staff die, but security guard Charles Campion manages to escape before the facility is locked down and takes his family out of the state.
After a couple of days, his car crashes at a gas station in Arnette, Texas. Bystanders and ambulance workers become infected by the dying Campion and his dead wife and child. The United States Army attempts to isolate Arnette, going so far as to execute civilians attempting to flee, but in vain – the virus, christened the "superflu" or "Captain Trips", spreads across the country. The government then has its agents (unknowingly) release the virus in the USSR, its satellite countries and China to avoid blame and retaliation. A global pandemic of apocalyptic proportions kills nearly everyone within a month. A prism of several personal tragedies describes the collapse of society, explosions of violence, the inability of the government and martial law to stop the near-extinction of humanity. Many of the few who are immune also die, unable to accept the loss of their loved ones or survive in a world where they must fend for themselves.
Stuart "Stu" Redman, one of the Arnette residents who encountered Campion, proves immune to the virus. He is forcibly held in a research center in Stovington, Vermont, in the hope that a treatment can be found. Stu escapes after the staff become infected, killing one man in self-defense. He meets sociology professor Glen Bateman and his dog Kojak, pregnant college student Frances "Frannie" Goldsmith, and overweight teenage nerd Harold Lauder. Stuart and Frannie are drawn to each other and eventually become lovers, to Harold's carefully concealed fury. Most survivors experience essentially the same two dreams. In one, a friendly 108-year-old black woman living in Hemingford Home, Nebraska, "Mother Abagail" Freemantle, invites them to her farm. They also dream of a terrifying "dark man" who calls himself Randall Flagg, among other things. People seek out one or the other. Stu and his group eventually meet Mother Abagail, who is convinced God has chosen her to do His will. The group travels to Boulder, Colorado, along with other survivors. These include Larry Underwood, a disillusioned pop singer; Nick Andros, a deaf-mute; Tom Cullen, a kind-hearted, mentally challenged man; Nadine Cross, a teacher in her 30s who is still a virgin; and Ralph Brentner, a good-natured farmer. As survivors continue to arrive, the group start organizing. They call their land the "Boulder Free Zone", reinstate law and order, bury Boulder's dead and restore electricity to the town.
Meanwhile, Randall Flagg, who possesses supernatural abilities, creates his own society in Las Vegas. His people worship him as a messiah and submit to his iron-fisted dictatorship. He has a drug addict and others who incur his displeasure crucified. Flagg rescues Lloyd Henreid, a mass murderer, from his prison cell and makes him his right-hand man. A pyromaniac nicknamed "the Trashcan Man" destroys oil tanks in Gary, Indiana, and travels to Las Vegas with a homicidal madman named "the Kid". The Trashcan Man finds stockpiles of weapons for Flagg, as Flagg prepares for war with the Free Zone. Mother Abagail, believing that she has sinned by being proud, goes into the wilderness on a spiritual journey without consulting anyone. In her absence, the Free Zone's leadership committee decides to secretly send three people to spy on Flagg, but Flagg already knows who two of them are. One dies in a shootout and the other is captured, but manages to kill herself to avoid revealing who the third (Cullen) is. Harold and Nadine secretly switch their allegiance to Flagg, and Harold plants a bomb in the house where the committee is to meet. The explosion kills seven or eight people, including Nick Andros and Susan Stern, but the other committee members are saved by the commotion caused by Mother Abagail's unexpected return and Frannie's too-late warning. Before dying, the extremely emaciated Mother Abagail reports God's will: Stu, Glen, Larry and Ralph (all of the surviving committee members except for the pregnant Frannie) must go to Las Vegas on foot to destroy Flagg. She also states that only three of them will get there. Harold and Nadine also set out for Las Vegas, but Harold has a motorcycle accident (caused by Flagg with his powers) on the way, and Nadine leaves him to die. Flagg comes to Nadine in the desert near Las Vegas and impregnates her; the horrifying experience (his face changed into that of a demon) causes her to lose her mind. Flagg brings her back to Las Vegas as his bride, but she manages to goad him into killing her and their unborn child. Stu breaks his leg en route to Las Vegas and persuades the others to go on without him. The remaining three are taken prisoner. When Glen refuses to grovel before Flagg, Lloyd kills him. Flagg gathers his people to witness the execution of the other two. Flagg conjures a small magical blue ball to kill Whitney Horgan, who can no longer stomach his evil. Moments before Larry and Ralph are to be torn apart, the Trashcan Man drags in a nuclear warhead (to try to atone for having blown up all of Flagg's experienced pilots). The blue ball grows enormously and resembles a hand — Ralph tells Larry it is "the Hand of God". Flagg vanishes just before it detonates the bomb, killing his followers, as well as Larry and Ralph.
The inhabitants of Boulder anxiously await the birth of Frannie's baby. They fear that the child will succumb to the superflu. Soon after her son is born, Stu returns, having been rescued by Tom. The baby contracts the superflu, but manages to fight it off. Stu and Frannie decide to leave Boulder and move to Ogunquit as society is slowly reestablished. The Complete and Uncut Edition includes an epilogue in which Flagg wakes up with memory loss somewhere in the Southern Hemisphere among a preliterate, dark-skinned people.