Henry is a friendly, highly determined nine- or ten-year-old boy living in a middle-class suburban neighborhood. Bored by his quiet street, he desperately wants a bicycle of his own but learns his parents cannot currently afford one. Refusing to wait, he exhibits a strong entrepreneurial spirit by launching his own "bicycle fund" and immediately searching for creative ways to earn money, starting with a massive abandoned stash of bubble gum.

Beatrice, universally known as Beezus, is a responsible and competent girl living on Klickitat Street. She serves as a loyal, practical friend to Henry, often helping him organize his business ventures, such as lending him her wagon to transport his found bubble gum and keeping his transaction records straight. Much of her daily life involves supervising her exasperating younger sister.

Ribsy is Henry's good-natured but perpetually troublesome dog. He acts as an agent of chaos on Klickitat Street, kicking off the story's events by stealing a neighbor's barbecue roast and nearly starting a dogfight. Despite the constant trouble and financial costs he causes, he remains Henry's most loyal companion.

Scooter is an older, independent neighborhood boy whose ownership of a bicycle and a newspaper delivery route gives him high status on the block. Henry views him as an arrogant show-off, though Scooter proves capable of both boasting and helpfulness, such as when he heroically retrieves a stolen roast from Ribsy.

Ramona is Beezus's highly energetic and stubborn little sister. She lives in her own world of imagination, frequently inventing games of pretend—such as acting like a mechanical toy that needs winding—that cause delays for the older children. Her childish demands and chaotic energy make her a constant, humorous nuisance to the neighborhood kids.

Robert is Henry's close friend and regular playmate. He shares Henry's middle-class, bicycle-less status and happily participates in neighborhood observations, such as watching the local adults bicker over cooking.

Mr. Grumbie is an adult resident of Klickitat Street whose backyard arguments provide free entertainment for the local kids. His attempt to host a barbecue is ruined when Henry's dog steals his raw meat, forcing him to sprint down the street in a chaotic chase.

Etta Grumbie is a neighborhood wife whose loud disagreements with her husband draw the attention of the local children. She serves as background color for the suburban setting of Klickitat Street.

Mary Jane is a young neighborhood girl. When Henry frantically asks for her help to stop a runaway dog carrying raw meat, she declines in order to keep her nice clothes clean.

Henry's mother runs the household and relies on her son to run local errands to the store. She is pragmatic about the family's finances and frequently expresses exhaustion over the constant messes caused by the family dog.

Henry's father is a practical, supportive presence in the household. He takes his son's entrepreneurial finds seriously, ensuring Henry operates within the rules before letting him launch his business.

The mother of Beezus and Ramona, Mrs. Quimby is tasked with managing the messy fallout of her children's neighborhood adventures.

Mrs. Wisser is an elderly resident of Klickitat Street. She enjoys conversing with the local children, though her friendliness sometimes inadvertently delays them when they are in a hurry.