The story begins in the town of Arnette, Texas. Charlie Campion crashes his car into a gas station. He is sick, delirious and dying. Charlie's wife and child are already dead in the car. Stu Redman, along with the other locals in Arnette, calls the paramedics. Little do they know that they are witnessing the outbreak point of a disease—later nicknamed the superflu or Captain Trips—that will kill over 99% of the world's population.
Stu Redman and a group of locals from Arnette are taken to the Centers for Disease Control and Prevention in Atlanta. Specialists race to find a cure for Captain Trips, and they think Stu Redman is the answer. He's the only person they've seen who is immune. They take him to their research facility. But the disease is more contagious than anyone can imagine, and despite their best efforts, it continues to spread across the country and even in the research facility. Stu is moved to another facility in Vermont.
While Stu is being studied and contained, Frannie Goldsmith and Harold Lauder watch their families die. They are also survivors. Though Frannie is pregnant, she stays long enough in Ogunquit, Maine, to bury her father. Harold, the little brother of one of her dead friends and one of her least favorite people in the town, accompanies her to try and find others.
Right before the outbreak, a deaf and mute young man named Nick Andros is robbed and beaten in Shoyo, Arkansas. The sheriff arrests two of the men who assaulted him, but the third man, who is also the sheriff's brother-in-law, evades capture. Nick watches as the superflu takes the entire town. Like other survivors, he has no symptoms and stays healthy. He does almost die when Ray Booth, the third man who attacked him, comes stumbling out of the woods where he had been hiding to evade capture, and tries to kill him.
Nick fights him off, but is wounded in his leg and eye. The infection from these two wounds almost kills him. The Walking Man comes to him in a fever dream and offers him life and more. Nick is offered the ability to hear. The young man is tempted, but refuses, because he knows the Walking Man is evil. Then he begins to dream of Abigail Freemantle, a black woman from Nebraska who is 108 years old. In his dream, she is singing old hymns. After Nick recovers somewhat from the infection and is heartened by the presence of Mother Abigail, he journeys to find her in Nebraska.
Another survivor, Larry Underwood, is a musician on the brink of real fame. His drug use is the only thing holding him back, so he goes to New York City to see his mother and clear his head. There he watches her die from the superflu in a hospital along with most of the city. After most are dead, he meets Rita Blakemoor, an older woman, and they begin a relationship.
But both Rita and Larry are deeply shaken by the superflu epidemic, and Rita becomes unstable after they find another survivor brutally murdered. They travel together for a time, but on the Fourth of July, Larry finds her dead from an overdose. He carries the guilt of her death with him, feeling that he should have tried to do more for her. He knew she was taking pills in an unhealthy way to deal with the tragedy, but he said nothing.
Stu Redman is still being kept as a prisoner in a medical facility in Stovington, Vermont. A man named Elder comes to kill him. Stu doesn't understand why anyone would want to kill him when so many are dying from the superflu, but he suspects it's so the U.S. government can deny being responsible — even though there is no government left. Stu kills Elder by beating him with a chair and then escapes from the facility.
Many survivors die of things other than the superflu. A young boy falls in a well, breaks his legs and dies alone. A crazed woman shoots a man in cold blood simply because she believes all men are rapists. A young woman puts the dead bodies of her son and husband in a freezer and enjoys going in and looking at them in triumph, glad to be rid of them. Unfortunately the door closes behind her on one of these visits, and she dies, trapped inside with them.
Stu finds Glen Batemen, a sociologist who taught at a small community college in Woodsville, New Hampshire. They notice that along with humans, the superflu took most of the domestic animals, such as dogs, but left wolves and wild animals untouched. Glen Batemen has one of the few surviving dogs. The sociologist declines to go with Stu initially but later joins his group.
Stu then encounters Frannie and Harold. Harold wants nothing to do with the Texan because he sees him as a threat to his hopeful romance with Frannie. Stu takes Harold aside and tells him he has no interest in Frannie; however, before long, Stu and Frannie fall in love.
Harold sees the two of them making love, and when rifling through Frannie's possessions, he finds a journal she was keeping for her unborn child. Frannie doesn't always speak kindly of Harold, and she makes it clear that she has no romantic interest in him. Harold becomes consumed with hate for Frannie — because she rejects his affections — and for Stu — because he took her when he said he wasn't interested. Harold vows to have revenge on them, but he pretends to accept their relationship.
Larry crosses the country alone for a time, fighting madness and guilt. Eventually two other survivors follow him. Nadine Cross is a beautiful, slightly older woman, who is taking care of a child she calls Joe. Joe had been left alone after the superflu killed his family. Nadine found him on the verge of death. She nursed him back to health, and she is the only person he trusts.
Joe doesn't speak, carries a knife and refuses to wear anything but underwear. They follow Larry because Joe doesn't trust him and even attempts to kill Larry while he's sleeping one night. Nadine saves Larry's life. Larry is aware that they are following him. But when they officially meet, the boy tries to kill him again.
Larry and Joe eventually make peace after Larry finds a guitar and sings one night. The boy stops picking up knives and takes the guitar. Larry and Nadine are shocked that the child is a talented musician. He even begins to speak and act more like a normal boy. Larry falls in love with Nadine, and though she cares for him greatly, she won't return his affection. Larry has no idea that Nadine is lusting after the Walking Man who visits her in her dreams.
The survivors all dream of the Walking Man, and many dream of Mother Abigail. They intuitively know that the Walking Man, whose current name is Randal Flagg, is evil, while Mother Abigail is the opposite, God's representative on earth. The survivors form groups and go to either Mother Abigail, who starts out in Nebraska but moves to Boulder, Colorado, or to Las Vegas, to be aligned with Randall Flagg.
Flagg’s first official follower is Lloyd Henreid. Flagg finds Lloyd left in prison and opens his cell, which keeps Lloyd from starving. Lloyd is grateful. He had been so hungry that he had begun eating another inmate, who died in the cell next to him. Lloyd isn't very bright, but Flagg makes him smart enough to become his right-hand man.
Randal Flagg's followers are more likely to be outsiders, like the man named Donald Elbert but called the Trashcan Man. He acquired the nickname for starting fires in trash cans and other places after his father murdered his siblings and tried to murder his mother and him. The local sheriff shot his father and then later married his mother. The two were divorced when the sheriff sent Donald to a mental hospital where he received electroshock therapy.
After the sickness took everyone, the Trashcan Man started fires all over the country, the bigger, the better, reducing whole towns to ash in his travels. He dreams of the Walking Man, and after wolves save the Trashcan Man, he pledges his life to Flagg. The Walking Man has the wolves on his side, among other animals, and can even enter ravens and other creatures to watch the survivors.
Nick runs into a man named Tom Cullen, who is slightly mentally disabled, but intelligent enough to save Nick from a tornado that Nick didn't see or hear coming. Nick is almost shot by a woman named Julie Lawry after refusing to sleep with her for a second time and not wanting her to join their duo. They go on to meet up with other survivors and are the first group to find Mother Abigail in Nebraska. They take her to Boulder.
Stu and his group are almost killed when a group of men who hold women captive and rape them tries to kill Stu, Glen and Harold. Along with the help of the women who were captives, they manage to kill the rapists.
Larry's group grows, and he follows Harold's signs all the way to the Boulder Free Zone, as the survivors rename the area. Larry idealizes Harold and uses the image as a source of strength and comfort on the trip, frequently asking himself what Harold would do when he's unsure. Lucy Swann joins their group. Though Larry is in love with Nadine, Larry begins sleeping with Lucy.
Once in the Boulder Free Zone, Nick, Stu, Susan Stern, one of the women rescued from the rapists, Larry, Frannie, Glen, and a friend of Nick's named Ralph, form the Free Zone Committee and are elected by popular vote. Their primary concerns are getting the power back on before winter, countering the threat of the Walking Man, clearing out the dead bodies and re-establishing society.
Mother Abigail commits the sin of pride by not confronting Nadine for the evil intent inside of her. She isn't right with God, so she leaves the Boulder Free Zone and goes wandering in the wilderness. The residents search but do not find her.
While she is gone, the committee sends spies out to collect information on the Walking Man. Larry asks his friend Richard Farris to go. Sue asks her friend Dayna Jurgens. Nick asks Tom Cullen. Tom is susceptible to hypnotism and is hypnotized to believe that he was driven out of the free zone. When the moon is full, he is supposed to return home.
In the Boulder Free Zone, Harold's hate for Stu and Frannie leads him to follow the Walking Man. Before he can join him in Las Vegas, he knows he must deliver a blow to the community. Harold has moments where he considers dropping his hate and becoming a new person. Many people in Boulder genuinely like Harold because he works hard and is good to people. Some men even nickname him Hawk.
But then the Walking Man tells Nadine to go to Harold and fulfill almost all of his sexual desires. Harold designs a bomb meant to kill the members of the Free Zone Committee. Right before Harold sets it off, Mother Abigail returns. News of her arrival brings most of the committee members outside before the bomb explodes. Only Nick and Sue on the committee are killed, though other innocent bystanders are killed as well.
Harold and Nadine take off to Las Vegas, but the Walking Man causes them to have an accident where Harold breaks his leg and is severely injured. Nadine knows that it has to happen this way and leaves him to die. Harold shoots at her before she goes, but the Walking Man interferes so she lives. Harold realizes the error of his ways. He writes down his apology and that he was deceived before he shoots himself.
A dying Mother Abigail meets with the remaining committee members. She tells them that Stu, Larry, Glen and Ralph must walk to the Walking Man in Las Vegas. Frannie is distraught. Mother Abigail heals her back, an injury she received when Harold's bomb went off.
The Walking Man comes to Nadine, and they have sex. Nadine is deeply disturbed by the Walking Man's evil and becomes pregnant. She eventually angers him on purpose, so he kills her.
The four committee members set off for Las Vegas. When they are more than halfway there, Stu breaks his leg in a fall. After much debate, the others leave him. Glen's dog stays with Stu as the others continue on.
Larry, Glen, and Ralph are picked up by the Walking Man's men and put in cells. Lloyd shoots Glen because he laughs at the Walking Man. Larry and Ralph are going to be ripped apart, but the Trashcan Man returns. He had to flee Las Vegas for blowing up some of the other men when they teased him. He comes back with radiation sickness, bringing a nuclear warhead. The Walking Man accidently sets off the bomb with a fireball that he creates. It explodes, killing everyone there.
Tom Cullen escapes before the bomb goes off, but the other spies are killed. Tom finds Stu and eventually they make it back to Boulder. Frannie has her baby, and they learn that the superflu doesn't kill all babies. Lucy has twins.
The Walking Man found a way to escape before the bomb went off and reappears in another part of the world to build his empire again.