Ramona Quimby is the protagonist of the story. She is a dynamic character who is seven years old and just starting to figure out who she really is. Ramona is filled with joy and energy and a sense of confidence that comes naturally to her. She is not afraid to speak her mind, nor does she shy away from strangers or a challenge. Ramona also makes several mistakes, which is natural for someone her age, but which also becomes a source of humiliation and shame for her as she starts to get older.

Ramona is initially seen writing out her Christmas list of all the different pets she would like to have. She does this in September, which shows that Ramona not only thinks ahead but also lacks patience (something her teacher points out as well). Ramona is known for getting herself into difficult situations, such as when she weaves a crown of burs into her hair or tells her teacher that she has wrinkly pantyhose. Ramona and her sister Beezus have a complicated bond, with Ramona often irritating Beezus intentionally. Ramona sees her sister as antagonistic, but it turns out that Ramona is the one perpetuating that type of relationship.