Claudia is a twelve-year-old girl who acts as the meticulous planner of her own runaway adventure. Highly organized and focused on rules, she feels bored by her monotonous suburban life and overshadowed by her younger brothers. She chooses the museum as her destination because she wants her escape to be elegant and comfortable, hoping the experience will help her return home a distinguished person.

Jamie is Claudia's nine-year-old brother, chosen specifically for the runaway mission because he stockpiles his allowance and card-game winnings. Unlike his sister, he takes a highly practical, frugal approach to the world and claims to enjoy complications. He acts as the treasurer for their trip, insisting on cost-saving measures like walking instead of paying for a bus pass.

Mrs. Frankweiler is a wealthy, 82-year-old widow who narrates the events of the story through a manuscript. She is a blunt, unconventional art collector who lives in a large, museum-like estate in Connecticut. Maintaining a keen mind that blends scientific observation with a deep appreciation for art, she takes an interest in the Kincaid children.

Saxonberg is Mrs. Frankweiler's lawyer and the recipient of her detailed narrative. He is described as being preoccupied with the law, taxes, and his ulcer. Mrs. Frankweiler frequently scolds him in her commentary for being boring and for failing to appreciate the arts, particularly noting his failure to ever visit the Metropolitan Museum of Art.

Kevin is Claudia and Jamie's six-year-old brother. He openly complains about walking with Claudia, preferring the company of his brother Steve, which contributes to Claudia's feeling of being unappreciated at home.

Steve is one of the Kincaid siblings, falling in age between Claudia and Jamie. He is part of the suburban family dynamic that Claudia leaves behind when she decides to run away.

Bruce is Jamie's school friend and regular seatmate on the bus. He frequently plays the card game War with Jamie, inadvertently providing Jamie with a source of income through his continuous losses.

Parks is Mrs. Frankweiler's butler at her Connecticut estate. He tends to the household's needs and assists his employer with her guests, occasionally using clever tactics to encourage reluctant visitors to eat their meals.

Sheldon is Mrs. Frankweiler's chauffeur. He handles transportation for her estate and maintains connections with staff at the Metropolitan Museum of Art.