In Stockholm, disgraced journalist Mikael Blomkvist is recovering from the legal and professional fallout of a libel suit brought against him by businessman Hans-Erik Wennerström, straining Blomkvist's relationship with his business partner and married lover, Erika Berger. Lisbeth Salander, a young, brilliant but antisocial investigator and hacker, compiles an extensive background check on Blomkvist for the wealthy Henrik Vanger, who offers Blomkvist evidence against Wennerström in exchange for an unusual task: investigate the 40-year-old disappearance and presumed murder of Henrik's grandniece, 16 year old Harriet. Vanger has been receiving every year a framed flower pressed, in the same style Harriet would do every year on his birthday before she disappeared, leading him to believe that he is being taunted by Harriet's killer. Blomkvist agrees, and moves into a cottage on the Vanger family estate on Hedestad Island.
Salander's state-appointed guardian, Holger Palmgren, suffers a stroke and is replaced by Nils Bjurman, a sadist who controls Salander's finances and extorts sexual favors by threatening to have her institutionalized. Unaware she is secretly recording one of their meetings, Bjurman brutally sodomizes her. At their next meeting, Salander tasers Bjurman, binds him, anally rapes him with a metallic dildo, and tattoos "I'm a rapist pig" across his torso. Using the secret recording she made, she blackmails him into securing her financial independence and having no further contact with her.
Blomkvist explores the island and interviews various Vanger family members, learning some were Nazi sympathizers during World War II. He uncovers a list of names and numbers that his visiting daughter, Pernilla, notices are Bible verse references. Blomkvist discovers that Salander had researched him illegally but, rather than report it, he recruits her as his research assistant. She uncovers a connection between the list and numerous young women brutally murdered from 1947 to 1967, indicating a serial killer; she also notes that many of the victims have Jewish names, theorizing that the murders could have been motivated by antisemitism. One morning, Blomkvist finds the mutilated corpse of his adopted cat on the doorstep. Another night, while walking outdoors, a bullet grazes his forehead; after Salander tends his wounds, they have sex. Blomkvist begins to suspect Martin, Harriet's brother and operational head of the Vanger empire. Salander also uncovers evidence that Harriet's late father, Gottfried, and later Martin, committed the murders.
Blomkvist breaks into Martin's house to obtain more proof, but Martin arrives and catches him. He forces Blomkvist into his specially prepared basement, knocking him out and placing him in restraints. Martin brags about killing and raping women for decades, as did his father, but makes it clear he does not know what happened to Harriet. As Martin is about to kill Blomkvist, Salander arrives, attacking Martin and forcing him to flee in his SUV. She pursues him on her motorcycle until he runs off the road and hits a propane tank, blowing up the car and killing him. Salander nurses Blomkvist back to health and tells him that, as a child, she was institutionalized after attempting to burn her father alive.
They deduce that Harriet is alive and in hiding; traveling to London, they confront Harriet's cousin, Anita, only to discover she is Harriet. Harriet reveals that Gottfried sexually abused her when she was 14 for an entire year before she was able to defend herself, accidentally killing him in the process. Martin continued the abuse after Gottfried died. Her cousin, Anita, smuggled her off the island and let Harriet assume her identity in London, though Anita and her husband were later killed in a car accident. Finally free of her brother, Harriet returns to Sweden and tearfully reunites with Henrik.
As promised, Henrik gives Blomkvist information against Wennerström, but it proves to be outdated and useless. Salander reveals that she had hacked Wennerström's accounts, and gives Blomkvist evidence of Wennerström's crimes, which Blomkvist publishes in a scathing editorial, ruining him and bringing Blomkvist to national prominence. Salander, in disguise, travels to Switzerland and removes two billion euros from Wennerström's secret accounts. Wennerström is later murdered in an apparent gangland shooting.
On her way to give Blomkvist a Christmas present, Salander sees him with Erika. She discards the gift and rides away on her motorbike.
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