At a government laboratory in California, a weaponized version of influenza is accidentally released, immediately wiping out everyone on staff except for military policeman Charles Campion and his family, who flee the base. However, Campion spreads the superflu, nicknamed "Captain Trips", to the outside world. One of the first sites of infection is at a gas station in East Texas where Stu Redman (Gary Sinise) and some friends have gathered. While the other townspeople become sick, Stu remains healthy and is confined at a CDC facility in Vermont order to study a possible cure. This proves futile and the superflu rages unchecked, causing civilization to collapse and killing over 99% of the population.
After the infection runs its course, a small group of immune survivors lies scattered across the country. These include rock star Larry Underwood, who has just had his big break but is now stranded in a New York City; Nick Andros a deaf man in the Midwest; Frannie Goldsmith a teenager in Ogunquit, Maine; Lloyd Henreid, a criminal stuck in a prison cell; and "Trashcan Man" a mentally ill scavenger. The survivors soon begin having visions, either from kindly Mother Abagail or from the demonic Randall Flagg. The two sets of survivors are instructed to either travel to Nebraska to meet Mother Abagail, or to Las Vegas to join Flagg.
As their journeys begin, Lloyd is freed from prison by Flagg in exchange for becoming his second in command. Trashcan Man, who is a pyromaniac, destroys a set of fuel tanks outside of Des Moines in order to win Flagg's favor. Larry escapes New York and meets a mysterious woman named Nadine Cross (Laura San Giacomo). Despite their mutual attraction, Nadine is unable to consummate a relationship with Larry because of her visions of Flagg, who commands her to join him as his concubine. Nadine eventually leaves Larry to travel on her own. Stu escapes from the CDC facility and gathers a group of survivors, including Frannie; Harold Lauder (Corin Nemec) a hometown acquaintance of Frannie's; and Glen Bateman (Ray Walston), a retired college professor.
As the group travels west, Harold grows frustrated at the way that Stu assumes leadership and grows close to Frannie. Meanwhile, Nick makes his way across the Midwest, eventually joined by Tom Cullen (Bill Fagerbakke) a gentle mentally challenged man. Eventually, Stu's group reaches Mother Abagail's farm in Hemingford Home, Nebraska. She tells them of a great conflict is imminent and that they must all travel on to Boulder, Colorado. There, the various survivors, including Nick, Tom, and Larry, join with others to form a new community based around Mother Abagail's teachings. Meanwhile, Flagg sets up his own autocratic society in Las Vegas.
Initially, all is well in Boulder. However, Frannie discovers that she is pregnant by her ex-boyfriend, causing her anxiety because she is not sure whether her child will be immune to the superflu. Meanwhile, Harold grows increasingly dissatisfied with his life in Boulder and begins experiencing visions from Flagg. He is soon seduced by Nadine, and decides to follow Flagg's dictates. Mother Abagail, now the spiritual center of Boulder, becomes convinced that she has fallen into the sin of pride, and leaves town to walk in the wilderness. Mother Abagail returns to town and, before passing away, tells Stu, Larry, Glen, and fellow council member Ralph Brentner that they must travel to Las Vegas to confront Flagg.
With winter fast approaching, the four men set out on their quest. While crossing a washed out road, Stu breaks his leg and stays behind while the others continue. Larry, Glen, and Ralph are soon captured by Flagg's forces and forced to endure a show trial before being executed. As they are being tortured, to the delight of Flagg's acolytes, Trashcan Man arrives with a stolen thermonuclear weapon. As Flagg transforms into a demonic visage, a spectral hand reaches out and detonates the bomb, destroying Las Vegas and apparently killing Flagg. Stu is rescued by Tom, who takes him to a nearby cabin to heal as winter sets in. They eventually return to Boulder in the midst of a blinding snow storm. Soon after being reunited with Stu, Frannie gives birth to a healthy baby; a daughter named in honor of Mother Abagail.