Crookes became interested in spiritualism in the late 1860s, and was most strongly involved around 1874–1875. Eric Deeson notes that Crookes's studies of the occult are related to his scientific work on radiometry in that both involved the detection of previously undiscovered forces.
Crookes was possibly influenced by the death of his younger brother Philip in 1867 at 21 from yellow fever contracted while he was on an expedition to lay a telegraph cable from Cuba to Florida. 
In 1867, influenced by Cromwell Fleetwood Varley, Crookes attended a séance to try to get in touch with his brother.
Between 1871 and 1874, Crookes studied the mediums Kate Fox, Florence Cook, and Daniel Dunglas Home. After his investigation, he believed that the mediums could produce genuine paranormal phenomena and communicate with spirits. Psychologists Leonard Zusne and Warren H. Jones have described Crookes as gullible as he endorsed fraudulent mediums as genuine.
The anthropologist Edward Clodd noted that Crookes had poor eyesight, which may have explained his belief in spiritualist phenomena and quoted William Ramsay as saying that Crookes is "so shortsighted that, despite his unquestioned honesty, he cannot be trusted in what he tells you he has seen." Biographer William Hodson Brock wrote that Crookes was "evidently short-sighted, but did not wear spectacles until the 1890s. Until then he may have used a monocle or pocket magnifying glass when necessary. What limitations this imposed upon his psychic investigations we can only imagine."
After studying the reports of Florence Cook, the science historian Sherrie Lynne Lyons wrote that the alleged spirit "Katie King" was at times Cook herself and at other times an accomplice. Regarding Crookes, Lyons wrote, "Here was a man with a flawless scientific reputation, who discovered a new element, but could not detect a real live maiden who was masquerading as a ghost". Cook was repeatedly exposed as a fraudulent medium but she had been "trained in the arts of the séance" which managed to trick Crookes. Some researchers such as Trevor H. Hall suspected that Crookes had an affair with Cook.
In a series of experiments in London, England at the house of Crookes in February 1875, the medium Anna Eva Fay managed to fool Crookes into believing she had genuine psychic powers. Fay later confessed to her fraud and revealed the tricks that she had used. Regarding Crookes and his experiments with mediums, the magician Harry Houdini suggested that Crookes had been deceived. The physicist Victor Stenger wrote that the experiments were poorly controlled and "his desire to believe blinded him to the chicanery of his psychic subjects."
In 1897, John Grier Hibben wrote that Crookes's idea of ether waves explaining telepathy was not a scientific hypothesis "he presents no facts to indicate its probability or to save it from being relegated to the sphere of bare conjecture."
In 1916, William Hope tricked Crookes with a fake spirit photograph of his wife. Oliver Lodge revealed there had been obvious signs of double exposure, the picture of Lady Crookes had been copied from a wedding anniversary photograph, but Crookes was a convinced spiritualist and claimed it was genuine evidence for spirit photography.
The physiologist Gordon Stein suspected that Crookes was too ashamed to admit he had been duped by the medium Florence Cook or that he conspired with her for sexual favors. He also suggested that Crookes had conspired with Anna Eva Fay. He noted that contrary to popular belief, Hope had been exposed as a fraud on several occasions. Stein concluded that all feats of Hope were conjuring tricks. In a review, biographer William Brock wrote that Stein made his "case against Crookes and Home clearly and logically."
Crookes joined the Society for Psychical Research, becoming its president in the 1890s: he also joined the Theosophical Society and The Ghost Club, of which he was president from 1907 to 1912. In 1890 he was initiated into the Hermetic Order of the Golden Dawn.