He was born in Philadelphia, Pennsylvania, son of Levi Horton Mudgett and his wife, formerly Theodate Page Price. His early criminal career (mostly using the pseudonym Dr. H. H. Holmes) was based on fraud and forgery, including a cure for alcoholism, real estate scams, and a machine that made natural gas from water.
He managed to secure a Chicago pharmacy and the property attached to it (by defrauding the pharmacist), and built a row of three-story buildings on it. The bottom floor was shops, the top his personal office, and the middle floor a maze of over one hundred windowless rooms. He called it The Castle and opened it as a hotel for the World's Columbian Exposition in 1893.
Women checked in, but they didn't check out. Over a period of three years, Mudgett tortured his selected victims in soundproof and escapeproof chambers which were fitted with gas lines that permitted Mudgett to asphyxiate the women at any time. Onced dead, their bodies went by chute to the basement, where they were either sold to medical schools or cremated.
He was discovered when a fire broke out at The Castle, revealing the carnage therein to the police and firemen, though he might have been caught eventually anyway, as he had taken out insurance policies on some of his victims before killing them.
The estimates placed the number of victims as between 20 to 100, including mostly women but some men and children. Mudgett (as Holmes) was put on trial for murder, and confessed to 28 murders (in Chicago, Indianapolis and Toronto) and 6 attempted murders. He was hanged in 1896 in Philadelphia.
He is the subject of the book Depraved: The Shocking True Story of America’s First Serial Killer by Harold Schechter.
On 8 July 1878 he married Clara A. Lovering of Alton, New Hampshire On 28 January 1887 he (bigamously) married Myrta Z. Belknap in Minneapolis, Minnesota; they had a daughter named Lucy. He filed a petition for divorce from his first wife after marrying his second, but it never became final. He married his third wife, Georgiana Yoke, on 9 January 1894.