Ramona is an energetic and highly imaginative five-year-old girl entering kindergarten at Glenwood School. Though often labeled a "pest" by her family, she merely has a strong desire to be noticed and understood by the people around her. She possesses a unique perspective on the world, evidenced by her doll named Chevrolet and her custom way of drawing the letter Q, and she fiercely defends her independence because she fears being treated like a baby.

Beatrice, known as Beezus, is Ramona's older sister who attends Glenwood School. She often views Ramona's imaginative antics as bothersome and ridiculous, frequently calling her a pest. As the older sibling, she represents the maturity that Ramona both admires and rebels against.

Mrs. Quimby is Ramona and Beezus's mother. She manages her younger daughter's spirited personality with a mix of patience and necessary firmness. She understands Ramona's need to make her own decisions, such as allowing her to stay home from kindergarten when she feels rejected by her teacher.

Miss Binney is the young, pretty kindergarten teacher at Glenwood School. She commands the affection and eagerness of her students, particularly Ramona. She is an observant educator who attempts to balance encouraging her students' imaginations with maintaining necessary classroom discipline.

Howie is a solid-looking boy with curly blond hair who lives in Ramona's neighborhood. He shares the daily walk to school with Ramona and sits in the same kindergarten class. He is generally sullen and practical, capable of modifying Ramona's tricycle into a two-wheeler with real tools.

Henry Huggins is an older boy at Glenwood School who wears a yellow slicker and serves as a crossing guard. He takes his duties seriously and is often accompanied by his dog, Ribsy. He frequently interacts with the younger children on their way to school and reluctantly steps in to help them when they get into trouble.

Mr. Quimby is the father of Ramona and Beezus. He provides a gentle, stable presence in the home and tries to engage with Ramona about her school troubles without making her feel pressured or interrogated.

Mrs. Kemp is Howie and Willa Jean's mother. She frequently coordinates walking the neighborhood children to school and acts as a mediator when disputes arise between Howie and Ramona over toys or ribbons.

Susan is a kindergarten student in Miss Binney's class. She has reddish-brown hair styled in thick, springy curls that bounce when she walks. She is generally well-behaved, keeps her white rainboots clean, and is repeatedly the target of Ramona's impulsive hair-pulling.

Davy is a quiet boy in Ramona's kindergarten class. He becomes the early subject of Ramona's intense romantic attention, leading him to spend much of his playground time running away from her attempts to kiss him.

Mary Jane is a friend of Beezus who enjoys acting like a mother figure to younger children. Ramona specifically avoids her help because she refuses to be treated like a baby on her first day of school.

Willa Jean is Howie's toddler-aged younger sister. She tags along with her mother when Mrs. Kemp walks the older children to school in the mornings.

Miss Mullen is the principal of Glenwood School. She handles student issues with a calm and sympathetic demeanor, gently escorting frightened students back to their classrooms rather than punishing them severely.

Mrs. Wilcox is a substitute teacher who covers Miss Binney's kindergarten class. She assigns easy drawing tasks rather than standard seat work, which Ramona quickly notices as irregular.

Ribsy is Henry Huggins's faithful dog. He often accompanies Henry on his traffic boy duties and inadvertently gives away Ramona's hiding spot behind the school trash cans by barking at her.