The Girl with the Dragon Tattoo is the first installment of a trilogy by Swedish author Stieg Larsson. Journalist Mikael Blomkvist, fresh from being convicted for libelling a wealthy Swedish financier, is hired by an elderly industrialist to find out who murdered his niece more than 40 years earlier. He joins forces with Lisbeth Salander, a young woman with multiple tattoos and piercings but also a talent for hacking into people's computers, and the two find themselves tracking a serial killer who has murdered women for several decades.

Mikael Blomkvist is forced to formally resign his position at Millennium, the financial magazine he co-founded with longtime lover Erika Berger, after being convicted of libelling financier Hans-Erik Wennerstrom. While awaiting the beginning of his two-month prison sentence, Blomkvist receives an unusual job offer. Henrik Vanger, an aging wealthy industrialist, wants him to live on his family's island compound for a year, ostensibly researching and writing a chronicle of the dysfunctional Vanger family, but actually investigating the disappearance and apparent murder of his great-niece, Harriet, more than 40 years earlier. Each year on his birthday, Vanger receives a pressed flower like the ones Harriet used to give him, and he believes her murderer is doing this to torture him. Having nothing better to do, Blomkvist reluctantly agrees to take the job and moves into a small house on Hedeby Island where he is surrounded by other houses occupied by various members of the large Vanger family.

In the meantime, Lisbeth Salander is carrying out her duties as an investigator for Stockholm-based Milton Security. Salander is an odd young woman with many tattoos and piercings but few social graces. However, she is an excellent investigator because she is also an expert computer hacker. She has recently done a thorough background check on Blomkvist at the request of Vanger's attorney, Dirch Frode, before Vanger offered him the job. Because of her troubled background and instability, the courts have placed Salander under the legal guardianship of attorney Nils Bjurman, who brutally rapes her. However, Salander, who lives by her own unique code of ethics, exacts revenge that includes forcing Bjurman to begin a process that will eventually release her from guardianship.

Blomkvist learns that Harriet vanished from Hedeby Island when she was 16 years old. The entire Vanger family had gathered for an annual business dinner, but a serious accident resulted in the bridge between the island and the mainland being closed for 24 hours, stranding everyone on one side of the bridge or the other. Vanger has concluded that Harriet was murdered by a family member because no one was able to get on or off the island during the hours surrounding her disappearance. During the course of his research, Blomkvist meets members of the Vanger family, including Harriet's brother Martin, who now runs the family empire; Cecilia, with whom Blomkvist has a brief affair; Martin's mother Isabella, who resents his poking into the family's history; and Henrik's brother Harald, a raging anti-Semite. He also learns about Gottfried, Harriet and Martin's father, a drunk who drowned many years ago.

Eventually Blomkvist decides he needs a research assistant to help him unravel the mystery of Harriet's disappearance and Frode recommends Salander. The two are puzzled by an entry in Harriet's diary that appears to be a short list of names and phone numbers, but they come to realize it is a list of women who were brutally murdered many years ago, along with Bible verses that describe how and why the women were killed. The trail eventually leads them to Gottfried Vanger, who raped and killed a number of women and taught his son Martin to do the same. Both men also raped Harriet, who drowned her father and in the confusion following the accident, escaped from the island with the help of her cousin Anita. After Salander saves Blomkvist, who has been imprisoned in Martin's basement torture chamber and is about to be killed, they find Harriet living on a sheep farm in Australia and convince her to return to Sweden since Martin has now been killed in an auto accident as he fled from the island.

Salander uses her computer hacking skills to help Blomkvist, who has become her lover, obtain the information he needs to bring down Wennerstrom's large criminal empire. She also uses her skills to steal millions from Wennerstrom, leaving him without the resources to pay off his mafia connections, and she reveals his whereabouts to someone who has him killed. Salander also realizes she is in love with Blomkvist, but as she is preparing to tell him, she sees him with Berger and, realizing they will always be together, simply leaves.