The novel starts with journalist Mikael Blomkvist, who is forced to resign his position at Millennium, a financial magazine he co-founded with his longtime lover Erika Berger, after being convicted for defaming the financier Hans-Erik Wennerstrom.
While waiting for his two month prison sentence, Mikael receives a job offer. Henrik Vanger, the retired C.E.O. of Vanger Corporation, wants him to live on his family's island compound for a year, as he investigates and writes about his dysfunctional family, but in reality he is investigating the disappearance and most likely death of his great-niece, Harriet, forty years ago.
Each year on his birthday, Henrik receives a pressed flower like the ones Harriet used to give him, and he believes her murderer is doing this to torture him. Mikael accepts the job and moves to a small house on the Hedeby Island where he is surrounded by the other members of the Vanger family.
Somewhere, Lisbeth Salander is working as an investigator for Milton Security. Salander is a young woman with tattoos and piercings. Lisbeth is an excellent investigator thanks to her computer hacking skills. Recently, she was hired to create a background search on Blomkvist, requested by Dirch Frode, the Vanger's attorney, way before Henrik had offered Mikael his job.
Due to Lisbeth's troubled background and incompetence, the court decided to place Lisbeth under the guardianship of Nils Bjurman. During one of their meetings Bjurman brutally rapes Lisbeth. However, Lisbeth decides to take revenge on him and he gave her full control of her life.
Mikael learned that Harriet vanished from Hedeby Island when she was sixteen-years-old. That day, the entire Vanger family had gathered for an annual business dinner. However, the dinner was interrupted by a serious car accident in the bridge that connected the island to the mainland. As a result, the bridge was closed for an entire day. Henrik is sure that one of his family members killed Harriet since nobody was able to get on or off the island for the entire day during her disappearance.
While investigating the story, Mikael meeting members of the Vanger family, starting with Harriet's brother, Martin, who now runs the family business. Then he met Cecilia, whom he had a brief affair with and Martin's mother Isabella, who resents him for barging in her family's history.
Eventually Blomkvist asked if he could hire a research assistant to help him with the disappearance of Harriet, so Frode recommends Salander. While investigating Harriet's diary, Mikael and Lisbeth are confused by the list of names and phone numbers. They later learn that the names are referring to women who were brutally murdered many years ago. Alongside the list there were Bible verses that described how and why these women were killed. The entire puzzle led them to Gottfried Vanger, father of Martin and Harriet, who killed and raped women and taught his son to do the same.
It was later revealed that both Martin and Gottfried raped Harriet. While escaping, Harriet drowned her father and later escaped the island with the help of her cousin Anita.
Later, Lisbeth saves Mikael, who was imprisoned in Martin's torture basement. Martin tries to escape the island by car, but was quickly pursued by Salander on her motorbike. During the chase, Martin crashed onto a truck and died.
After these events, Lisbeth and Mikael found Harriet living on a sheep farm in Australia and convinced her to return to Sweden now that Martin is dead.
Lisbeth used her computer skills on her new lover, Mikael Blomkvist, in order to obtain information to expose Wennerstrom's criminal empire. While hacking Wennerstorm, she decides to steal millions from him, leaving him without any resources to pay for his mafia. Also, she released his location information to someone who wants him dead.
Later, Lisbeth realized that she was in love with Mikael, but when she was about to tell him, she saw him with Erika Berger and realized that he was never going to be with her and left.