The story centers on four people: Dr. Lionel Barrett, a physicist with an interest in parapsychology, his wife Edith, and two mediums: Florence Tanner, a spiritualist, and Benjamin Franklin Fischer, who had visited the haunted house 30 years prior.

Barrett, Tanner, and Fischer are hired by dying millionaire, William Reinhardt Deutsch, to investigate the possibility of life after death for a week.

During the investigation, various influences begin to affect each character's personal weaknesses: Florence through her belief in spiritualism and her over-eagerness to rid the house of its evil; Dr. Barrett through his almost-arrogant disbelief in/disregard for spiritualism, his debilitated physical condition (having suffered from polio when young), and his belief in science and the power of the Reversor machine he has built to rid the house of its haunting; Edith through her personal fears, insecurities, and pent-up sexual desires; and Fischer through his deliberate inaction (which he calls "caution").

In 1973 the novel was made into the film The Legend of Hell House, starring Pamela Franklin, Roddy McDowall, Clive Revill, and Gayle Hunnicutt.

The story was also adapted as a comic book mini-series, Richard Matheson's Hell House, written by Ian Edginton, with art by Simon Fraser.