In the fictional town of Stonetown, an 11-year-old orphan named Reynie Muldoon takes a series of strange tests. His tutor at the orphanage, Miss Perumal, has helped him register for the tests, which promise “special opportunities” for gifted children. The exams are full of riddles, puzzles, and personal questions about the test-taker’s bravery. Reynie manages to solve all the riddles, and he answers the question about his courage with honesty: he hopes he is brave, but he is not sure.
Outside the building of the second test, Reynie encounters a girl named Rhonda, who loses her pencil. Since the children are only permitted to bring one pencil, she doesn’t have a spare. Reynie breaks his pencil in half and offers her the sharpened end, reasoning that he can sharpen his half so they can both take the test. Rhonda thanks him and offers to help him cheat, but Reynie turns her down. He is the only child in his section to pass the test. After the second test, Reynie meets the other children who have passed: Sticky Washington, a nervous boy with a perfect memory; and Kate Wetherall, a cheerful and athletic girl who carries a red bucket full of various useful items. They discuss the tests and realize that helping Rhonda was a test in itself. The three children are brought to the third test, in which they have to cross a multi-colored tiled floor without setting foot on a blue or black square. They all pass and are led through an underground passage by a sad-looking man named Milligan. When they emerge from the tunnel, Milligan disguises himself and requests that they wait on the porch of a nearby house. He leaves, and the children tell each other about themselves. Kate reveals that she is an orphan like Reynie—her mother died when Kate was a baby, and her father abandoned her when she was two years old.
Rhonda emerges from the house, revealing that she is not a child but a young woman. She introduces the children to their final test, a maze, and she mentions that they should be able to complete it with their eyes closed. This hint helps Reynie realize that he can navigate the maze by feeling the arrows etched into panels throughout the maze. All three children make it through the maze.
Afterwards, Rhonda and the tests’ administrator, a woman known only as Number Two, bring the children inside to eat dinner and meet Mr. Benedict. Mr. Benedict is the man who created the tests; he is friendly and intelligent, and he suffers from narcolepsy, a disorder that causes abrupt sleeping spells. He informs them that they are waiting on Constance Contraire, the final child who passed the tests, who did so by breaking all the rules and answering every question with rude poetry. When Constance arrives, Mr. Benedict explains that he is assembling a group of children to fight a great danger. He asks if the children can guess what they all have in common, and Reynie notes that all four are alone. Mr. Benedict agrees—Reynie, Kate, and Constance are orphans, and Sticky is a runaway. Mr. Benedict uses a machine he invented to reveal hidden messages encoded in television and radio transmissions, which causes the public to panic and which has thus resulted in what the news calls the Emergency. He explains that he needs people with a powerful love of truth to fight the Sender of these messages, and they must be children because the Sender, a man named Mr. Curtain, operates out of the Learning Institute for the Very Enlightened, a school on Nomansan Island. The children will go to the Institute as students and investigate. They agree to join the mission. In the days leading up to their departure, they practice Morse code and name themselves the Mysterious Benedict Society. They learn that Milligan was once a secret agent who had his memory stolen by the Sender’s henchmen, and that the Sender is preparing to increase the strength of his messages.
Rhonda brings the children to the Institute, where they are greeted by Jackson and Jillson, a pair of Executives (the high-ranking staff of the Institute). Maintenance duties at the Institute are performed by employees called Helpers. Jackson and Jillson explain that Executives are former students who performed well as Messengers, which is a role granted to top students. Messengers’ duties are kept secret from the other students, but the Mysterious Benedict Society infers the Messengers deliver the transmitted messages.
On their first day of classes, the children are greeted by Mr. Curtain, and they are horrified to see that he is identical to Mr. Benedict, save for the addition of a wheelchair and mirrored sunglasses. They send a message in Morse code to their associates on the mainland asking if Mr. Benedict has deceived them, and the response is a riddle that, when solved, reveals that Mr. Curtain is Mr. Benedict’s estranged twin brother.
As classes continue, Reynie and Sticky excel, which earns them an enemy in competitive student and Messenger Martina Crowe. They witness a student be punished with a trip to the “Waiting Room,” which terrifies him and in turn worries Reynie and Sticky. Sticky is especially afraid of being sent to the Waiting Room. A few days later, all four children suffer terrible headaches and irritability, and they realize they are being affected by the signal of a transmitted message as Mr. Curtain increases the power. Constance is able to hear the voice of the Messenger, indicating that she possesses an unusually sensitive mind. They send a Morse message with these developments to the mainland, and, to their dismay, Mr. Benedict requests that the children begin cheating on assignments so they can earn the rank of Messengers. They do so, but their names are not on the next list of Messengers. Reynie encounters Mr. Curtain, who expresses an approval for Reynie and remarks that he sees similarities between them. Mr. Curtain also explains that Messengers will soon be obsolete when Mr. Curtain brings about what he calls “the Improvement.”
As the children continue investigating, they learn that the Helpers are former enemies of Mr. Curtain’s, whose memories he has erased (he calls the process “brainsweeping”). Reynie starts to doubt himself, but he recalls a conversation with Mr. Benedict when the older man told Reynie that people can create their own families, which renews Reynie’s dedication to his friends. Their espionage is going well until Sticky is caught cheating and brought to the Waiting Room. That night, Sticky returns to the dorm, traumatized and covered in mud. He has to speak with Mr. Curtain the next day, and he doesn’t believe that he will be able to withstand the pressure and avoid giving up his friends. Reynie reassures him and comes up with a plan. When Sticky meets with Mr. Curtain, he lies that Martina Crowe abused her power as a Messenger to force him to cheat. This takes suspicion off Sticky—but instead of being punished, Martina is rewarded with a promotion to Executive. Sticky and Reynie become Messengers, and Jackson blindfolds them and brings them to the Whispering Gallery. There, they see the device that Mr. Curtain uses to transmit messages and to brainsweep his enemies: the Whisperer. The Whisperer eases its user’s greatest fears, and both Reynie and Sticky are unable to resist it. The next day, the Mysterious Benedict Society searches for the Whispering Gallery. Instead, they find a room containing Mr. Curtain’s plans to end the Emergency with the Improvement and install himself as “Minister And Secretary of all the Earth's Regions” (M.A.S.T.E.R.). They also find a room full of brainsweeping machines.
That night, Milligan arrives on the island to help the children. He offers to take them home, but Kate insists that their work isn’t done, and the others agree. Milligan accepts this and informs them he will stay hidden by the shore, where they can leave him messages. Reynie is struggling against his desire to return to the Whisperer, so he doesn’t argue when Kate decides to look for the Whispering Gallery by herself. She eavesdrops on a conversation between Mr. Curtain, Jackson, and Jillson, but Mr. Curtain suspects her presence, and she only barely manages to escape. This puts Mr. Curtain on alert for a spy. Reynie suggests that to defeat Mr. Curtain, all four of them need to take him on at once. To ensure that Reynie and Sticky will be called for Messenger duty, the children tamper with the cafeteria food and give all the other students food poisoning. Reynie leaves a note informing Milligan of their plan, but the note is discovered. Milligan sacrifices himself to the Executives in order to destroy the note and keep the children safe, and the Executives imprison him in the Waiting Room.
Mr. Curtain summons Reynie and Sticky to the Whispering Gallery for the final round of messages before the Improvement. Reynie asks Sticky to take the first turn with the Whisperer so he can resist it and stall for time. Sticky is afraid that Mr. Curtain will discover his subterfuge and brainsweep him, but he trusts his friend, so he does as Reynie asks. While Mr. Curtain is distracted with the Whisperer, Reynie signals to Mr. Benedict that they need Kate and Constance, and Mr. Benedict sends a message to the girls. They run to the Whispering Gallery, but Martina Crowe and Jillson decode the Morse message and chase after them. After a long chase, Kate gives herself up to save Constance.
Meanwhile, Reynie takes his turn with the Whisperer. Thinking of his friends, he manages to resist it. Constance comes in through the window, and Milligan arrives to rescue Kate, having escaped from the Waiting Room. He reveals that he has regained his memories and remembers that he is Kate’s long-lost father. Mr. Curtain rages at the children, and Reynie provokes him until Mr. Curtain falls asleep. Like Mr. Benedict, he has narcolepsy, and Mr. Curtain’s sleeping fits are triggered by rage. Kate arrives as Mr. Curtain wakes up, and the children realize they have to strap into the Whisperer to destroy it. Constance takes on the task, using her stubbornness to confuse the Whisperer. She succeeds. Mr. Benedict, Rhonda, Number Two, and Milligan enter from a hidden door. Mr. Benedict remains to finish dismantling the Whisperer, and the others take Mr. Curtain down to the group’s boat. As they board, he escapes, but his Whisperer is destroyed, and his plans are foiled.
The group returns to Mr. Benedict’s house. Reynie is reunited with Miss Perumal, and Sticky is reunited with his parents, who have been tirelessly searching for him. Miss Perumal adopts Reynie, and Mr. Benedict adopts Constance. All four children have found families, and they celebrate their victory with a snowball fight.