Ramona is an energetic and imaginative nine-year-old girl living on Klickitat Street in Portland, Oregon. She is fiercely independent and deeply values fairness, which frequently puts her at odds with strict adults. She tries hard to be cooperative and helpful at home, though her impulsive nature sometimes leads to friction with her older sister. She feels highly sensitive to the unpredictability of the adult world, particularly concerning her mother's pregnancy and her father's career changes.

Beezus is Ramona's older sister. She takes on significant responsibility in the Quimby household, including stepping up to babysit Ramona after school. She frequently finds her little sister's antics irritating and tries to assert parental authority over her. At the same time, Beezus serves as a crucial confidant for Ramona and actively shields their parents from unnecessary stress.

Mrs. Quimby is the patient, hard-working mother of Beezus and Ramona. She works at a doctor's office to support the family financially while her husband studies. She is a comforting, steady presence who validates her daughters' emotions and tries to maintain a positive outlook despite the physical discomforts of a new pregnancy and the family's tight financial constraints.

Mr. Quimby is the kind, perceptive father of the Quimby girls. He works at a local grocery store while studying to become an art teacher, a career transition that causes him significant anxiety. He uses silly jokes to manage his stress and keep the family's spirits up. He remains deeply supportive of his daughters' emotional needs and listens calmly to their problems.

Aunt Beatrice, often called Aunt Bea, is Mrs. Quimby's sister and a third-grade teacher. She connects easily with her nieces and brings a lighthearted, fun energy to the Quimby household. Her developing relationship with Uncle Hobart introduces significant changes and bustling excitement to the family's daily routine.

Uncle Hobart is Howie Kemp's uncle who works in the oil industry. He initially alienates Ramona by playfully teasing her and calling her Howie's girlfriend, a joke she strongly dislikes. Despite this rocky start, he proves to be generous, eager to please his new extended family, and highly involved in organizing major family events.

Howie is Ramona's best friend and next-door neighbor. He is a practical, active boy who spends his time riding his bicycle and learning to ride a unicycle. He is less emotionally sensitive than Ramona and often views formal family events as an annoying disruption to his playtime.

Mrs. Kemp is Howie's grandmother and the neighborhood babysitter who watches Ramona after school. She runs a strict household and sometimes assigns blame unfairly. Her stern demeanor pushes Ramona to advocate for staying home alone with Beezus instead.

Willa Jean is Howie's messy, sometimes difficult younger sister. Ramona tries to be kind to her out of sympathy for the "littlest child," though she often finds the requirement to entertain her exhausting and unfair.

Picky-picky is the elderly Quimby family cat. His passing requires the girls to step up and handle a difficult situation independently in order to spare their pregnant mother from unnecessary emotional stress.

Roberta is the newest addition to the Quimby family. Her impending arrival causes Ramona significant anxiety about losing her place as the baby of the family, though anticipating the new baby ultimately brings the siblings closer together.

The girls' grandfather travels to Portland to participate in the family's major celebrations. He adds a touch of excitement to the proceedings by treating his granddaughters to rides in a chauffeured limousine and promising them pizza.