The novel opens with a disorienting prologue: an unnamed narrator lies in an outdoor cage, his back ruined, speaking with a shadowy captor who tells him he is going to die. The narrator wants oblivion but admits he kept his memory, "Especially the parts I didn't want" (2). The rest of the novel reveals how he ended up in that cage.
In the summer of 1935, Frank Nichols, a 36-year-old former history professor and World War I veteran, arrives in Whitbrow, a small rural town in Georgia, with his lover Eudora (Dora), a younger woman with mismatched eyes, one grey and one green. They pose as a married couple. Frank has inherited a house from his late aunt, Dorothy McComb, who left a letter begging him to stay away: "there is bad blood here, and it is against you" (29). Unemployed and desperate after losing his professorship at the University of Michigan when his affair with Dora was discovered, Frank ignored the warning. He plans to write a book about his great-grandfather, Lucien Savoyard, a Confederate cavalry officer and slave speculator of legendary cruelty who was killed by his own slaves after the Civil War. Dora will teach at the local school.
Frank befriends Lester Gordeau, a young man who works at his father's feed shop, and Lester's father, Old Man Gordeau, the town's mayor and patriarch. He also encounters Martin Cranmer, a reclusive, sharp-tongued taxidermist who lives in a fortified cabin between town and river and drops cryptic warnings about the woods to the east.
A monthly ritual called the Chase of Pigs anchors the town's life: Two healthy hogs are herded into the deep woods as an offering. The pastor frames the ritual as biblical, but Frank senses something pagan beneath the veneer. When Frank crosses the river alone and pushes into the woods, a thin, pale mixed-race boy of about 13 appears. The boy throws stones with startling accuracy and smiles to reveal teeth filed to points. Frank flees to Martin's cabin, but Martin, barricading himself inside on the night of the full moon, orders Frank away.
The town votes to end the pig ritual, persuaded by Dora's suggestion to use straw effigies. Martin warns that something eats the pigs and might come to town if they stop.
Consequences arrive swiftly. On the next full moon, 10-year-old Tyson Falmouth, son of local farmer Miles Falmouth, goes out to investigate a disturbance at his father's hog pen and is killed and eaten. Sheriff Estel Blake summons lawmen from the neighboring town of Morgan. Old Man Gordeau's dogs track a scent across the river to a bald, muscular black man who once visited the general store. The man is captured and hanged. Estel, wracked with doubt, later tells Frank that something went wrong during the lynching, though the Morgan men never explained what.
Weeks later, Dora arrives at school to find 20 corpses exhumed from the cemetery and tied upright to classroom chairs. Above the blackboard, the words "SEND THE PIGS" are scrawled in dark earth. The creatures across the river have made their demands explicit.
A first expedition of 15 armed men crosses the river. Saul Gordeau, Lester's 17-year-old brother, vanishes from the column and is found the next morning blindfolded, gagged, and wearing an iron slave collar fitted with bells. He tells Frank privately that the creatures carried him underground, assaulted him, and that one transformed from man to animal under his hand.
Martin reveals what Frank needs to know: Silver wounds the creatures permanently, fire kills them, and anything else heals almost instantly. Frank has silver-tipped bullets made and plans to flee. Meanwhile, Sheriff Blake abandons his post, and Buster Simms, the biggest man in town, is appointed acting sheriff. Families begin leaving Whitbrow.
Frank and Dora marry at a courthouse in the mill town. On their wedding night, the creatures attack. Frank finds Dora's student and young neighbor, 14-year-old Ursie Noble, with her hand bitten off, her mother killed. At home, one creature bites deeply into Dora's heel. Another charges up the staircase, and Frank fires his antique cannon loaded with Dora's silver flatware, killing it. In the morning, the dead creature is a naked man.
Dora's wound vanishes impossibly fast. Her appetite turns ravenous for organ meat, and she begins sleepwalking. Ursie dies at the hospital, where doctors observed infant-sized fingers regrowing from her stump before the director ordered her cremated.
A second expedition of nine men and three dogs ends in catastrophe. The stone-throwing boy, now wearing a red dress, lures the dogs to their deaths. Arthur Noble, Ursie's father, is killed by the creatures. Old Man Gordeau dies from a comrade's panicked gunshot. The boy transforms into a wolf before the men's eyes after an axe blow to his head heals instantly. Buster is killed. Frank is captured and carried to the ruined Savoyard Plantation.
Frank wakes naked in a cage. From an upper window he sees Dora standing with Hector, the bald black man, once Savoyard's blacksmith and now leader of the creatures. Hector reveals the full history: Savoyard was a werewolf, centuries old, who hunted his own slaves on full moons and bought replacements under the guise of speculation. Hector deduced that silver could kill him, forged a silver-tipped spear, and led the revolt, but Savoyard bit Hector while dying, turning him. Dora came to the plantation willingly: "She knew what she was now. And she came to be with her own" (271–272). Hector has Frank flogged on the same wheel once used on slaves, forcing him to recite the names of Savoyard's victims. His vengeance is displaced: He cannot hurt Savoyard anymore.
Martin Cranmer, revealed as a werewolf who chose never to transform, sets fire to the plantation and frees Frank. Dora appears with Frank's gun. Martin carries Frank to his cabin with superhuman speed, fights off the creatures with flaming moonshine and burning books, and dies buying them time.
The town rejects Frank and Dora. Shopkeepers lock their doors. Only one-armed Mike, a regular at the general store, helps by bringing a wheelbarrow. Dora has been shot with a silver bullet, which prevents her from healing. Frank drives out of Whitbrow but crashes near Chalk Ridge, a Black sharecropping community. An elderly healer named Miss Matilda takes them in. Dora expels the bullet and recovers. Matilda, recognizing what Dora has become, makes Frank promise to leave before the full moon.
Driving north, Frank locks Dora in a cabin bathroom as the full moon rises. Through the keyhole he watches her transform. She breaks out through a window. In the morning he finds her in bed, blood-matted, beside a pile of vomit containing a chewed baby shoe. Frank puts the gun to her head and pulls the trigger, but his wrist jerks at the last instant. He drives alone to Chicago.
There, Frank connects Martin's persistent cough, caused by lungs that never healed despite his regenerative powers, to a key realization: The creatures' lungs can be permanently burned. He recruits John "Granny" Giangrande, an old friend who became an army chemist specializing in poison gas during the war, and Karl Eicher, a down-on-his-luck Marine veteran. Granny synthesizes mustard gas. The three return to the now-abandoned Whitbrow and, the day after the full moon, throw gas jars into the creatures' underground den. They shoot the emerging creatures with silver bullets. Hector kills Eicher before Frank wounds him. Frank buries Eicher and leaves Georgia.
In a closing coda, Frank is an aging man with an alcohol addiction, walking with a cane in Chicago, his book unwritten. He spots Dora across a street, still young, holding hands with the mixed-race boy. The moon is waxing toward full. Frank believes she will come for him and ask how many legs he wishes to walk on, an echo of the Sphinx's ancient riddle. The novel ends with Frank contemplating his answer, suspended between mortality and monstrousness.