Ramona is an energetic, highly imaginative second grader living on Klickitat Street in Portland. Caught between early childhood and a desire to be viewed as mature, she is highly sensitive to adult opinions and hates being laughed at. She notices the financial and emotional stress within her household and longs for reassurance from her working mother, often expressing her anxiety through impulsive actions like squeezing an entire tube of toothpaste into the sink.

Mrs. Quimby is Ramona and Beezus's mother. She works full-time as a receptionist to help support the family after her husband's period of unemployment. She balances the exhausting demands of her career with managing the household and raising two daughters, a load that leaves her physically and emotionally drained. Though she loves her family deeply, her fatigue occasionally makes her seem distant to Ramona.

Beatrice, known as "Beezus," is Ramona's older sister and a seventh grader entering adolescence. She is generally viewed as sensible, responsible, and helpful around the house, which contrasts sharply with Ramona's impulsivity. Her growing maturity allows her to understand more about their parents' financial struggles, though she also experiences typical teenage frustrations about her appearance and wearing hand-me-down clothes.

Mr. Quimby is the father of Ramona and Beezus. After a stressful period of unemployment, he works as a grocery clerk, a demanding job that leaves him tired and frustrated by difficult customers. He struggles to adjust to the shifting domestic power dynamics now that his wife is working full-time and expects him to share cooking duties.

Willa Jean is the preschool-aged sister of Ramona's friend Howie. Because Mrs. Quimby works, Ramona spends her afternoons at the Kemp house and is expected to entertain Willa Jean. The toddler is impulsive, destructive with toys, and constantly fawned over by adults, a dynamic that deeply irritates Ramona.

Mrs. Rudge is the substitute teacher for Ramona's second-grade class. She is plump, soft, and emphasizes hard work, famously telling her students that "can't" is not a word. Her strict approach to spelling causes Ramona to worry about her teacher's true opinion of her, though Mrs. Rudge proves to be highly observant and empathetic to her students' distress.

Howie is Ramona's friend and Willa Jean's older brother. He and Ramona spend their afternoons together at his house under his grandmother's supervision. He shares Ramona's desire to escape his younger sister's annoying behavior, often retreating to the basement to build things from scrap wood and glue.

Mrs. Kemp is Howie and Willa Jean's grandmother. She provides after-school childcare for Ramona while Mrs. Quimby works. She insists that the older children include Willa Jean in their games and swiftly manages the chaos when their basement construction projects go awry.

Mrs. Swink is an elderly woman who attends the Quimbys' celebration brunch. She persistently calls Ramona "Juanita" and treats her like a much younger child, prompting Ramona to politely hide her irritation rather than correct the adult.

Denise is a student stylist at the local teaching salon. She offers a discounted haircut to Ramona while Beezus gets her hair styled behind a privacy screen. She treats Ramona to a luxurious shampoo and gives her a pixie cut that earns praise from the other stylists.

Mrs. McCarthy is a guest at the Quimbys' party. She casually remarks that Beezus is growing up to be a "mother's girl," a comment that inadvertently sparks intense jealousy and self-doubt in Ramona regarding her own place in the family.