Set against the turbulent backdrop of London in 1888, this dark crime thriller follows the investigations of
Mary Kelly (Heather Graham) and her small group of London prostitutes trudge through unrelenting daily misery. When their friend Ann Crook (Joanna Page) is kidnapped, they are drawn into a conspiracy with links higher up than they could possibly imagine. The kidnapping is soon followed by the gruesome murder of another woman, Martha Tabram (Samantha Spiro); and it becomes apparent that they are being hunted down, one by one as various prostitutes are murdered and mutilated post-mortem.
The murder of Martha and her companions grabs the attention of Whitechapel Police Inspector Frederick Abberline (Johnny Depp), a brilliant, yet troubled, man whose police work is often aided by his psychic "visions." His colleague, Sergeant Peter Godley, tries to grasp his friend's wild theories. Abberline's investigations reveal that the murders, while gruesome, imply that an educated person is responsible due to the precise and almost surgical method used. Ann is found a few days later in a workhouse having been lobotomized after officials and doctors supposedly found her to be insane.
It is implied this was done to silence her. Abberline consults Sir William Gull (Ian Holm), a physician to the Royal Family, drawing on his experience and knowledge of medicine. During this meeting it is revealed Abberline is struggling with opium addiction. Gulls findings, coupled with his superiors impeding his investigations, point Abberline to a darker and more organized conspiracy than he originally thought.
Abberline becomes deeply involved with the case, which takes on personal meaning to him when he and Mary begin to fall in love. Abberline deduces that Freemason influence is definitely present in these crimes. His superior, a high ranking Freemason himself, then makes direct intervention and suspends Abberline. It is then revealed that Gull is the killer. He has been killing the witnesses to painter Albert Sickert (Mark Dexter)'s forbidden Catholic marriage to Crook, who bore his legitimate daughter Alice.
Sickert is actually Prince Albert, grandson of reigning Queen Victoria (Liz Moscrop), and therefore Alice is heiress to the British throne. Gull tells Abberline that "mankind will remember him for giving birth to the 20th century." Abberline draws his gun, but before he is able to shoot Gull, he is knocked out by one of Gull's henchmen.
Gull tries to have Abberline eliminated without leaving any witnesses, but Abberline fights back and kills two of the assassins by overturning a carriage. Gull himself is a Freemason and his increasingly sinister behavior lends an insight into his murderous, but calculated, mind. Rather than publicly charge Gull, the Freemasons decide to lobotomize him to protect themselves and the Royal Family from the scandal.
Gull defiantly states he has no equal among men, remaining unrepentant up to his lobotomy, resulting in him becoming invalid just as Ann had been.
Abberline tries to save Mary, but arrives too late, and blames his superior for not helping him or Godley on the cases. Abberline does nothing but watch Mary's mutilated body being taken away.
Abberline receives a mysterious letter, which he soon realizes is from Mary, but he decides not to look for her as a way to offer her protection, as the Freemasons may be watching his every move. Abberline decides to burn the letter, knowing that he can never have a normal life.
Mary Kelly does not die; Gull earlier mistook Ada, whom Liz said was from France (but is from Brussels in Belgium), for Mary and he kills her instead. Mary lives with Alice in a cottage on a cliff by the sea. Abberline is found dead of an opium overdose, knowing he can never see Mary again without endangering her. Sergeant Godley comes to pay his respects for the Inspector.