Ramona is an exuberant six-year-old preparing to enter the first grade. She prefers imaginative play and creative expression over rigid rules, famously inventing a game involving smashing old bricks into red dust. Her strong desire to be brave and grown up conflicts with her anxiety over her mother's new job and the daunting environment of Room One. She longs to be understood by the adults in her life and struggles to control her impulsive reactions.

Beatrice is Ramona's responsible, orderly older sister who is entering the sixth grade. She attempts to establish a mature identity by dropping her childhood nickname and dealing with peer teasing. Although she sometimes finds her younger sister embarrassing, she increasingly demonstrates solidarity with Ramona and validates her intense feelings about being laughed at.

Dorothy Quimby is the pragmatic matriarch of the family, balancing household management with a new job as a bookkeeper at a doctor's office. She loves her daughters equally, though she sometimes inadvertently dismisses Ramona's most intense feelings. She works to guide her children through conflicts, teaching them about accountability and emotional regulation.

Mr. Quimby is the primary earner of the family who provides a vital sense of stability for Ramona. Although he is frequently away at an office job or out bowling, his presence profoundly settles the emotional atmosphere of the home. He shares an artistic inclination with Ramona and helps foster her confidence through his steadfast affection.

Mrs. Griggs is a traditional first-grade teacher who prioritizes orderliness and diligent seatwork. Her strict classroom management style contrasts strongly with the freedom Ramona experienced in kindergarten. She struggles to accommodate kinesthetic learning styles and creative impulses, leading to friction with energetic students.

Howie is a young boy who lives down the street from the Quimbys and serves as Ramona's closest neighborhood playmate. He is practical and literal-minded, casually refusing to corroborate Ramona's exaggerated story about a hole in her house. Despite occasional fallouts, he remains a steady companion.

Susan is an orderly first-grade student who successfully conforms to classroom expectations. She closely mimics Ramona's unique design during a paper bag owl craft project, inadvertently becoming a source of intense frustration and conflict.

Miss Binney is a young kindergarten teacher remembered fondly by her former students. She is highly sensitive to the emotional needs of young children, setting a high standard for kindness that Ramona uses to measure all future educators.

Mr. Cardoza is an engaging sixth-grade teacher who drives a red sports car and incorporates wordplay into his lessons. He is highly admired by the older students and provides a crucial moment of kindness that restores confidence in younger children who cross his path.

Davy is a first-grade student who struggles with verbal fluency and reads words backward. His academic difficulties evoke empathy from his peers, prompting unauthorized attempts to assist him during independent work time.

Mrs. Kemp is Howie's grandmother, who occasionally serves as a babysitter for the Quimby girls. She is a pragmatic caregiver who knits sweaters for her dog and prefers watching television over entertaining energetic children.

Mrs. Miller is the school secretary who handles administrative tasks and lost items. She provides a sympathetic ear and adult validation when students recount exciting neighborhood encounters.

Willa Jean is a younger neighborhood child who accompanies her family on visits. She remains largely in the background while the older children invent elaborate games.