Having qualified as a homeopath, Crippen started to practise in New York, where in 1894 he married his second wife, Corrine "Cora" Turner (stage name: Belle Elmore), born Kunigunde Mackamotski to a German mother and a Polish-Russian father. She was a would-be music hall singer who openly had affairs. In 1894 Crippen started working for Dr Munyon's, a homeopathic pharmaceutical company. In 1897, Crippen and his wife moved to England, although his US medical qualifications were not sufficient to allow him to practise as a Doctor in the UK. As Crippen continued working as a distributor of patent medicines, Cora socialised with a number of variety players of the time, including Lil Hawthorne of The Hawthorne Sisters and Lil's husband/manager John Nash.

Crippen was sacked by Munyon's in 1899 for spending too much time managing his wife's stage career. He became manager of Drouet's Institution for the Deaf, where he met Ethel Le Neve, a young typist, around 1903. After living at various addresses in London, the Crippens finally moved in 1905 to 39 Hilldrop Crescent, Camden Road, Holloway, London, where they took in lodgers to augment Crippen's meagre income. Cora cuckolded Crippen with one of these lodgers, and in turn Crippen took Le Neve as his mistress in 1908.

Crippen's defence maintained that Cora had fled to America with another man named Bruce Miller and that Cora and Hawley had been living at the house since only 1905, suggesting a previous owner of the house was responsible for the placement of the remains. The defence asserted that the abdominal scar identified by pathologist Spilsbury was really just folded tissue, for among other things, it had hair follicles growing from it, something scar tissue could not have; Spilsbury noted that the sebaceous glands appeared at the ends but not in the middle of the scar.

Other evidence presented by the prosecution included a piece of a man's pyjama top supposedly from a pair Cora had given Crippen a year earlier. The pyjama bottoms were found in Crippen's bedroom, but not the top. The fragment included the manufacturer's label, Jones Bros. Curlers, with bleached hair consistent with Cora's were found with the remains. Testimony from a Jones Bros. representative, the store that the pyjama top fragment came from, stated that the product was not sold prior to 1908, thus placing the date of manufacture well within the time period of when the Crippens occupied the house and when Cora gave the garment to Hawley the year before in 1909.

Crippen was born in Coldwater, Michigan, to Andresse Skinner (died 1909) and Myron Augustus Crippen (1827–1910), a merchant. Crippen studied first at the University of Michigan Homeopathic Medical School and graduated from the Cleveland Homeopathic Medical College in 1884. Crippen's first wife, Charlotte, died of a stroke in 1892, and Crippen entrusted his parents, living in California, with the care of his two-year-old son, Hawley Otto.

Throughout the proceedings and at his sentencing, Crippen showed no remorse for his wife and concern for only his lover's reputation. After just 27 minutes of deliberations, the jury found Crippen guilty of murder. He was hanged by John Ellis, assisted by william Willis, at 9 a.m. on 23 November 1910 at Pentonville Prison, London.

In 1981, newspapers reported that Sir Hugh Rhys Rankin claimed to have met Ethel Le Neve in 1930 in Australia and that on that occasion, she told him that Crippen murdered his wife because she had syphilis.

In October 2007, Michigan State University forensic scientist David Foran claimed that mitochondrial DNA evidence showed that the remains found beneath the cellar floor in Crippen's home were not those of Cora Crippen. This research was based on genealogical identification of three matrilineal relatives of Cora Crippen (great-nieces, located by U.S. genealogist Beth Wills), whose mitochondrial DNA haplotype was compared with DNA extracted from a slide with flesh taken from the torso in Crippen's cellar. This has raised new questions about the identity of the remains found in the cellar, and – by extension – over Crippen's guilt.

In December 2009, the Criminal Cases Review Commission, having reviewed the case, declared that the Court of Appeal will not hear the case to pardon Crippen posthumously.

These recent arguments for Crippen's innocence have been disputed by some commentators. It has been argued that the DNA sample could have been tainted or mislabeled, or alternatively that the putative relatives were not actually blood relatives of Mrs. Crippen. The research has since been published in the January 2011 issue of the Journal of Forensic Sciences.

The research team also argued that a scar on the abdomen of the body, which the Crown Prosecution interpreted as a scar consistent with one Mrs. Crippen was known to have, convincing the jury that the remains were Mrs. Crippen’s, was incorrectly identified, because the tissue had hair follicles, whereas scars do not (a point which Crippen's defence argued at the time).