A good-hearted, unusually gifted orphan named Reynie Muldoon enters a competition to win a scholarship to the prestigious Boatwright Academy. While undergoing a grueling series of tests, Reynie joins forces with two other uniquely gifted orphans, Sticky Washington and Kate Wetherall, and the three of them work together to tackle the challenges in their path. The children are introduced to a fourth gifted orphan, Constance Contraire, and finally to the enigmatic Mr. Benedict.

Mr. Benedict lays out the world-changing stakes of his top-secret mission to Reynie, Sticky, Kate, and Constance: The Emergency is out of control, and the only way to stop it is to infiltrate the mysterious L.I.V.E. Institute on Harbor Island. Our young heroes embark on an undercover operation as transfer students at the school, and learn to navigate unfriendly fellow students, bizarre, nonsensical classes, and a shockingly familiar Headmaster.

The kids of the Mysterious Benedict Society come to a grim realization about Dr. Curtain's methods of keeping secrets. They also learn the dire consequences to the mission if they were to slip to the bottom of their classes: they would be kicked out. After receiving a message from the children, Mr. Benedict and his crew investigate his possible connection to Dr. Curtain. The children resolve to learn more about the elite Messenger program at the school.

The children make a risky play to search for clues right under Dr. Curtain's nose. Mr. Benedict and Milligan head out into rugged terrain to do some recon of their own. Rhonda and Number Two butt heads about their unique approaches to fighting The Emergency. Sticky gets caught trying to help Kate cheat, and finds out the next phase of Dr. Curtain's insidious plot. Kate suffers a blow to her academic standing but finds a saving grace in Martina Crowe and her tetherball team.

Reynie and Sticky investigate secret transmissions. Constance and Kate explore the island.

Mr. Benedict reveals the truth about his past with Dr. Curtain - and how he may be partly to blame for Curtain's misdeeds. The adults agree the mission has gotten too dangerous to continue. Sticky is given a special task during Messenger duty and begins to question his loyalties. Kate and Reynie develop their respective friendships with Martina and Curtain's son, SQ, and use them to advance the mission.

Kate embarks on a rogue mission into Dr. Curtain's secret lab which ends in disaster. Mr. Benedict, Number Two, and Rhonda decide to take matters into their own hands. Reynie accuses Sticky of being taken in by Dr. Curtain's charismatic ways, while Kate's deception makes Martina a target. Reynie is called into Dr. Curtain's office for interrogation. Constance's unique sensitivity to the Whisperer comes to a head, and the team realizes that their time is running out.

Mr. Benedict, Rhonda, and Number Two arrive at The Institute, ready to take down Dr. Curtain and his minions. The kids form an elaborate plan to destroy the Whisperer once and for all. Milligan's shocking connection to Dr. Curtain is revealed. Dr. Curtain prepares to take an aggressive step forward in The Improvement. The kids, Benedict's team, and Dr. Curtain face off in a climactic final showdown, the fate of society itself hanging in the balance.