The novel opens with Jack Reacher, whose nose is broken from his last adventure (Worth Dying For), heading for Virginia, trying to get a ride out of Nebraska, hitch-hiking in the middle of the night, without any car stopping for him. After an hour and a half of waiting, two men and a woman let him climb in and even ask him to help drive part of the way. They introduce themselves as Donald McQueen, Alan King, and Karen Delfuenso. Reacher notices that the car's occupants tell him lies for no obvious reason and that the woman is very nervous. They ask him to take the wheel for a while as they rest from shifts at driving. McQueen and King sleep, though Karen does not. They pass two roadblocks where the highway police are searching for one or two males in dark suits who killed a man and took off in a Mazda. The Mazda is subsequently found with fingerprints; it is then believed by FBI agent Julia Sorenson and Sheriff Victor Goodman that after the murders the men went to a car park behind a nightclub, where they kidnapped a cocktail waitress (Delfuenso) and stole her car, an Impala.

Karen repeatedly blinks, giving Reacher coded messages—which he manages to decode—and learns that the two men in the car are the wanted people the police are looking for and that Karen has been taken as hostage. Sorenson and Goodman's theory is proven correct after they visit a gas station and examine the security camera footage facing across the street. After a stop for gas Reacher buys coffee for the group, but before doing so uses the store's phone to alert the cops. Sorenson, the closest to the area, drives over, but by then the group have left. McQueen becomes suspicious and tells Reacher to use his bank card (which is a fraud) to rent rooms for the night. In the motel lobby McQueen fires his gun at Reacher and misses. McQueen, King, and Karen flee.

Reacher is apprehended by Sorenson, whose boss wants Reacher arrested. Sorenson is about to do so, but gets a call that a vehicle is on fire nearby. Going to the location, they find a car on fire with an unidentified body in it. They assume it is the body of Karen Delfuenso. On the way to Sorenson's office, Reacher manages to pull her gun from her holster and tells her to drop him off a mile away from the office. However, Sorenson is told by Goodman that Lucy Delfuenso, Karen's daughter, has been kidnapped. Goodman explains he had told Lucy her mother was missing (she was at her friend's/neighbor's house), and suggested Lucy's friend's mother stay home. Lucy's friend's mother went to work, leaving the children home alone, and Lucy was kidnapped. They also later learn that some terrorist threat against the United States might be involved in these events. Then they learn that the whole case has been closed as if it never happened, for some sort of over-riding national security reason. Reacher and Sorenson agree together to try to solve the case and catch the fugitives.

Karen has not been killed as expected but reveals herself as an undercover agent with the FBI, and says that the body in the car was King. The other fugitive, McQueen, is also an undercover special agent with the FBI who tried to infiltrate a terrorist group called Wadia which has threatened to pollute a huge drinking water aquifer with nuclear waste. Reacher, Lucy, Sorenson, Karen, and the eyewitness from the beginning of the novel have all ended locked up in some sort of witness-protection compound. Knowing that McQueen has gone off radar, Sorenson, Karen, and Reacher escape the compound to try to save him. They are eventually able to locate the terrorists' hiding place, a huge ex-army missile storage bunker. Sorenson is killed by a sniper. Despite Karen's protests, Reacher enters and kills the gang one by one, in retaliation for Sorenson.

He comes upon Peter King, Alan King's older brother, who wants revenge for his brother's death. McQueen might have been killed otherwise if he had not lied and said Reacher killed Alan. Reacher plays along and soon manages to kill Peter, but the thin cord binding McQueen takes time to saw through with a key and the remaining members of the group are all about to attack. Crucially assisted by Karen Delfuenso at a fatal juncture, Reacher, McQueen and Karen successfully escape. The terrorist threat turns out not be as serious as was thought, because the group only claimed to possess damaging material. In reality, there only existed some empty trailers from the time of the cold war that had been forgotten in the bunker, but had never been used for nuclear material. However the non-existent radioactive material was being used by Wadia as a sort of virtual currency they could be use in trading with terrorist groups, making their whole establishment a terrorist network's "bank". Before setting out for Virginia Reacher explains to McQueen the answer to a question Reacher had asked Alan King earlier in the book: "Can you talk non-stop for a minute without using the letter A?". The answer is you can do it by counting from one to one hundred. The first letter "A" occurring in "one hundred and one".

The novel is a sequel to Worth Dying For, despite its predecessor being The Affair which is a prequel novel. The following novel is Never Go Back and is a sequel, not prequel, to Worth Dying For and A Wanted Man in the series continuity, unlike The Affair.

The book was a commercial success selling over a million copies worldwide and was No. 1 on many booksellers' lists for numerous weeks. However, it received mixed reviews. Many enjoyed the book, but thought its ending was too detailed and disagreed with its criticism of the United States' comprehensive security response to 9/11. The novel also criticized the CIA for being inept and lazy, while the FBI is given a far more favorable judgment.

• Lee Child introduces A Wanted Man - Jack Reacher book 17 on YouTube
• A Wanted Man: A Jack Reacher Novel by Lee Child on YouTube