Mikael Blomkvist (Daniel Craig), co-owner and writer of Millennium magazine, has just lost a libel case against crooked businessman Hans-Erik Wennerström, for which he must pay 600,000 Swedish kronor (approximately 87,000 USD) in damages. Meanwhile, Lisbeth Salander (Rooney Mara), a researcher for Milton Security and a computer hacker, has compiled a very extensive background check on Blomkvist for Henrik Vanger (Christopher Plummer), retired CEO of Vanger Industries, for a job that Henrik wants him to do. Despite the recent scandal, Salander passes Blomkvist as “clean.”
Blomkvist receives a phone call from Henrik’s lawyer, Dirch Frode (Steven Berkoff), summoning him to the Vanger estate at Hedeby Island in Hedestad. Blomkvist reluctantly meets Henrik, who offers him two jobs: to write a Vanger family history, and, using the information provided by Henrik for the memoir, to solve the murder of his niece Harriet Vanger, who disappeared almost 40 years previously; Henrik is convinced that one of the family killed her. He reveals that someone he believes to be the killer has been sending him pressed flowers, which Harriet had always given him on his birthday. He says he will pay Blomkvist handsomely for this job, but Blomkvist agrees only when he promises to give him damning information about Wennerström, who is Henrik’s former employee.
Meanwhile, Salander, who is a ward of the state, despite being in her twenties, due to diagnosed mental incompetency, goes to visit her legal guardian, Holger Palmgren, only to discover that he has suffered a stroke. Her new guardian, lawyer Nils Bjurman (Yorick van Wageningen), seizes control of Salander’s finances and issues her a monthly allowance, which angers Salander, as Palmgren allowed her to manage her own finances.
Blomkvist gets to work right away, staying in a cottage that Henrik provides. He draws up a family tree of all of the living members of the Vanger family. He receives a visit from Harriet’s cousin Cecila Vanger (Geraldine James), who tells him that her sister, Anita, was much closer to Harriet than the rest of them. Blomkvist visits Anita (Joely Richardson), who is living in London, and tells Blomkvist that she can’t help him either: she escaped the family when she was eighteen, but Harriet never made it to eighteen. Blomkvist finds Harriet’s notebook, containing the names of five women with a 5-digit number next to each of their names. Gustav Morell (Donald Sumpter), a retired policeman, says that they are telephone numbers that are unrelated to the names listed next to them. However, when Blomkvist gets a surprise visit from his daughter Pernilla, she hints that the numbers relate to Bible verses. Blomkvist returns to the cottage to find that each Bible verse comes from the book of Leviticus and describes methods of killing, opening up the first lead on the case in 35 years. Blomkvist’s co-worker and lover Erika Berger (Robin Wright) visits him and tells him that because of the financial straits Millennium is in, they will be out of business within a few months. Henrik and his nephew, current Vanger Industries CEO Martin Vanger (Stellan Skarsgård), decide to invest in the magazine. Shortly afterwards, Henrik suffers a heart attack, and the Vanger family asks Blomkvist to stop investigating their family affairs.
Meanwhile, Salander is mugged in a subway station and her laptop is damaged when she fights back. Salander asks Bjurman for some extra money for a replacement computer. Bjurman agrees on condition that she performs fellatio on him. A few nights later, Salander claims to need more money for groceries, and is told to meet Bjurman at his apartment. Bjurman handcuffs Salander to the bed, then rapes and sodomizes her. Without Bjurman’s knowledge, Salander has recorded the rape on a hidden camera. A few nights later, she arranges to meet him again at home and renders him unconscious with a taser. Upon waking up, Bjurman finds himself tied and bolted to the floor, naked. Salander then tortures him and shows him the video of her rape. She blackmails him, demanding that he allow her to have full access to her finances again, write glowing monthly reports about her behavior, and apply to have her status of legal incompetency rescinded, or she will post the rape video on the Internet. In addition, Salander tells Bjurman that if she should find out a woman is ever in his apartment again, she will kill him. To make sure he remembers the deal, she tattoos the words, “I AM A RAPIST PIG” on his torso.
Blomkvist begins looking for a researcher to help him find out more about the Bible verses. Frode recommends Salander, whom Blomkvist learns did the background check on him. Upon seeing the incredibly detailed report, he discovers Salander hacked into his computer. He then visits her apartment, making her an offer to help him find Harriet’s murderer, to which she agrees. As Salander traces the Bible verses to a series of murders occurring from the late 1940s to the mid 1960s, Blomkvist finds a series of photos of a parade held in Hedestad which Harriet attended on the day that she disappeared. The photos suggest that she saw something that frightened her. He spots a couple in the crowd taking pictures around the same time and tracks down the woman who took the pictures; after locating and reviewing the photos, they find a picture of a man in a blue school uniform staring at Harriet.Salander’s research reveals that all of the women murdered had Jewish, or more specifically, Biblical names; linking the murders to several members of the Vanger family who were members of the Swedish Nazi Party. During the investigation, Salander and Blomkvist become lovers.
The next night, Salander looks through family archives examining Harriet and Martin’s late father and Henrik’s nephew, Gottfried, particularly his travels from the 1940s through the 1960s to see if he was in the same towns as the women at the same time they were murdered. Meanwhile, Blomkvist meets Harald, Henrik’s other brother and a former Nazi, and asks to see some pictures he took on the day Harriet disappeared. Blomkvist asks Harald to identify a man in one of the pictures who has a similar jacket and face to the man in the parade photo. Harald immediately identifies him as Martin. Salander continues researching and finds that Gottfried visited every town that each woman was murdered in at the same time they were murdered, but is puzzled that one murder took place two years after Gottfried died. However, she sees that Martin was studying in Uppsala, where the murder was committed, at the time. She deduces that Gottfried “initiated” Martin into being a serial killer when she finds a picture with the two of them attending a conference in one of the towns where a murder was committed, and Martin’s picture matches the one on the parade photo.
Blomkvist attempts to break into Martin’s house for more clues, but is caught by Martin, who leads Blomkvist into his basement at gunpoint and gasses him. Blomkvist wakes up to find himself hung by his neck. Martin brags about killing dozens of women over several years, but angrily denies killing his sister. Martin then tries to suffocate Blomkvist, but Salander, having missed Blomkvist and gone looking for him, sneaks up behind Martin and strikes him with a golf club. After freeing Blomkvist, she gives chase to Martin on her motorcycle. Martin crashes his car, which ends up on its side as gasoline leaks from the ruptured tank. Martin dies in the explosion as the gasoline ignites on the hot engine.
With the help of two hacker friends, Plague and Trinity, Blomkvist and Salander discover that Harriet (Joely Richardson) has been living in London under Anita Vanger’s identity to hide from Martin. Anita helped her escape the island in her car and the two used Anita’s maiden name and her married name until Anita and her husband died, leaving her identity all to Harriet. Blomkvist finds Harriet and she tells him that she killed her father, who had been sexually abusing her for years, and that Martin saw her do it. Martin then began repeatedly raping her until Henrik sent him to a boarding school in Uppsala. When he returned on the day of the parade, she fled Sweden with the help of her cousin, Anita. The framed flowers sent to Henrik on his birthday were sent by Harriet, who intended them as a sign of her well-being. Finally free of her brother, Harriet returns to Sweden and has a tearful reunion with Henrik. As promised, Henrik gives Blomkvist the information on Wennerström, but Blomkvist is dismayed to find out that the information is too old to legally incriminate him, as the statute of limitations has expired, and not shocking enough to turn the public against him. Salander hacks into Wennerström’s computer and finds information regarding his involvement with illegal arms and drug trafficking, which she gives to Blomkvist to publish.
The article propels Millennium into stardom and destroys Wennerström. Salander uses her hacking skills to access Wennerström’s numerous bank accounts and then travels around Europe in disguise as Wennerström’s assistant, converting all of the money to bonds which she places into several accounts of her own. From this she ends up with 2 billion euros. Wennerström is eventually murdered by his shady associates. Salander visits her old legal guardian, Palmgren, telling him she’s found “a friend” he would approve of. She buys Blomkvist a Christmas present of a nice leather coat but on her way to give it to him she spots Blomkvist and Berger walking together happily. Heartbroken, she tosses the jacket in a nearby dumpster and rides off through the streets of Stockholm.