A couple has bought a family portrait at a charity auction. As they go upstairs, the father in the painting comes to life. The husband activates the security alarms and locks up the place, and his wife is in bed as her door opens. The husband comes in and finds her dead, covered in blood. Then something approaches and kills him.
Dean and Sam are at a bar and Dean is collecting phone numbers. Sam notices a story in a paper about the murder, in upstate New York, and it matches a pattern their dad knew about. They drive there and check out the place but the house is clean – literally. The couple's property is at an estate sale and the Winchesters go there passing themselves off as art dealers. The art house owner's daughter, Sarah, comes down and she and Sam hit it off, but then her father chases them out. Dean has Sam call Sarah to have dinner and pump her for information. He gets the provenances, the papers on the items, from Sarah, and matches up one item – the painting – to the murdered victims.
Dean and Sam break into the art house warehouse to burn the picture. They remove it from the frame and take it outside and set it on fire. Back at the warehouse, the picture reassembles itself in its frame. The next morning Dean realizes he left his wallet at the warehouse. They go back to get it and Sarah spots them, while Dean finds his wallet and leave them together. Sam spots the painting and he and Dean go to a researcher to get background on the murders, and how the father Isaiah killed his family by cutting their throats with a razor. They get a photo of the painting and notice the father has moved. Sarah confronts her father who is selling the painting despite her reluctance.
Dean is pushing Sam to keep on seeing Sarah and get over his dead girlfriend Jessica. Sam gives in and calls Sarah and finds out they've sold the picture. Sam gets the address from her and they head for the house of the woman Evelyn who bought it. She's reading a book when Isaiah comes out of the picture and attacks her.
Dean and Sam arrive and Sarah shows up as well, and they break into the house to find her dead, her head nearly severed from her neck. Sarah lies that she was the only one there and Sam explains to her what's going on. She insists on going with them, feeling responsible for selling the picture. They break back into the house and examine the painting, and Dean notices the position of the razor has changed. There's also a different painting in the background, of a mausoleum that says Merchant.
They check out several cemeteries until they find the mausoleum and a doll inside a glass case next to the child's crypt. The father's urn is missing and while Dean checks the records, Sam and Sarah talk about Sam's track record of people getting hurt around him and how he lost Jessica. Dean interrupts to reveal Isaiah was buried separately, and buried rather than cremated so there are bones to burn. They dig up the coffin and burn the body, then go back to Evelyn's house to burn the painting. Sam and Sarah go in and notice that the little girl has disappeared from the painting along with the razor…and the door swings shut.
They figure the girl is the killer and try to find something to repel the ghost with while Dean tries to get in. The girl shows up, carrying her doll from the mausoleum. Dean grabs an iron poker and manages to drive it off. Sarah figures out the doll is the key as it has some of the girl's real hair. Dean heads for the mausoleum while the ghost girl manifests again and slams a desk into Sam, disarming and trapping him. The ghost closes on Sarah as Dean manages to ignite the doll's hair, and the girl disappears in a burst of flame.
Later Dean puts it together that the girl was adopted and killed her original family, then Isaiah took her in and she killed his family as well. The Winchesters are ready to leave and Sarah points out that since she's alive, maybe he's not cursed. Sam says he'll come back. He leaves…then returns for one goodbye kiss.