Edgar Freemantle, a Minneapolis contractor, barely survives a horrific on-site accident where his truck was crushed by a crane. Freemantle's right arm is amputated, and severe injuries to his head cause Edgar to have problems with speech, vision, and memory. As a result, Edgar also has violent mood swings and thoughts of suicide. During one of those mood swings, he attacks his wife, who later claims that as a main reason why she divorced him.
On the advice of his psychologist, Dr. Kamen, Edgar takes "a geographical" - a year long vacation meant for rest and further recovery. He decides to rent abeach house on Duma Key, a small island off the west coast of Florida, after reading about it in a travel brochure. Edgar's beach house is located on a part of the island called Salmon Point; Edgar nicknames the house "Big Pink," because of its rich pink color. On the advice of Dr. Kamen, Edgar revives his old hobby of sketching after he moves into Big Pink. He settles in with the help of Jack Cantori, a local college student.
Edgar becomes obsessively involved in his art, painting with a furious energy and in a daze. Edgar brings up psychic images in his paintings; he learns that his younger daughter, Ilse, is engaged to a choir singer and that his ex-wife is having an affair with his former accountant by painting these situations. While exploring the island with a visiting Ilse, Edgar drives past an elderly woman, Elizabeth Eastlake. Ilse becomes violently ill as they drive into an overgrown part of the island. Elizabeth later calls Edgar, warning him that Duma Key "has never been a lucky place for daughters". Edgar initially disregards the message, since Eastlake has Alzheimer's disease.
Edgar slowly recuperates helped in part by taking longer and longer walks along the beach. He slowly approaches and eventually meets and befriends a man in his late 40's whom Freemantle had seen sitting under an umbrella off in the distance. This character, Jerome Wireman, to whom Edgar becomes quite close, is a hired companion for Eastlake. As it turns out during the conversation, Miss Eastlake is very wealthy and owns half of the island, while the other half is a subject of dispute.
The way Edgar paints becomes systematic: he gets a phantom-limb sensation and he paints a psychic image. He eventually compiles a large catalog of artwork and is convinced by his friends to try to sell it to an art gallery; he does and the gallery plans to exhibit his work. While the exhibition is being planned, Edgar gradually begins to understand that his paintings have a paranormal power that allow him to manipulate events, places and people. But nobody outside of Edgar's close family and friends will ever know this. It is evidenced when one of his paintings removes a bullet that was lodged in Wireman's brain from a previous suicide attempt, and another causes Candy Brown, a man accused of raping and murdering a young girl in a highly publicized case, to die suddenly in his prison cell. Elizabeth advises Edgar that due to the power they possess his paintings should be removed from the Island after the exhibition.
Elizabeth makes a surprise appearance at the exhibition, and after seeing the paintings herself for the first time becomes distressed and tells Edgar a number of things, including that the "table is leaking". Elizabeth suffers a violent seizure as she is trying to tell Edgar this and dies in the hospital soon after. Edgar suspects that the entity, Perse, silenced Elizabeth. When Edgar returns to Duma the next day he discovers that Big Pink was broken into and finds a canvas with "Where our sister?" sprawled on it, left in the house along with the footprints of an adult and two children. He soon discovers that those in possession of his paintings either die, or become possessed by "Perse" and carry out her deeds, which mainly include killing people close to Edgar. Most notably, Mary Ire, who had purchased one of a series of "Girl and Ship" paintings, breaks into Ilse's apartment and kills her by drowning her in her bathtub (just minutes after Ilse burns "The End of The Game" at Edgar's request). Mary Ire commits suicide almost instantly thereafter.
Edgar begins to realize that his paintings are connected to tragic events in Miss Eastlake's childhood. Edgar discovers, through both his paintings and the drawings done by a young Elizabeth after she had suffered a head injury and began drawing herself, that Elizabeth had inadvertently used her paintings to discover a figurine off of the coast of Duma Key. This figurine, of a red-cowled woman, used the young Elizabeth to begin changing the reality around her. Elizabeth tried to use her power to destroy the figurine by drawing it and then erasing it. This only enraged the entity Persephone, which then killed Elizabeth's twin sisters by leading them into the surf and drowning them. A young Elizabeth, with the help of her Nanny, eventually discovered that the entity could be neutralized by drowning her in freshwater, and Elizabeth was able to do this by placing the figurine in a cask that is sealed in a cistern under the original house on Duma Key.
Intent on putting a stop to Perse following the death of his beloved daughter, Edgar, along with Wireman and Jack, travels to the house Elizabeth lived in as a child, which is now overgrown by thick, unnatural vegetation. They manage to find the figurine, and are able to contain it in freshwater inside one of their flashlights. Later, Edgar takes the flashlight back to Big Pink, where his daughter Ilse begins to form out of the sand and seashells under the house. The entity offers Edgar immortality and forgetfulness in exchange for the flashlight. Edgar, however, has a different flashlight and tricks the entity masquerading as his daughter to get close enough to him that he can destroy it. Later, Edgar drops the figurine into one of the freshwater lakes of Minnesota.
The book ends with Edgar starting his final painting; a storm destroying Duma Key.