Ramona Quimby, Age 8, is a story of a young third-grader's experiences as she starts a new school year at a new school and deals with family stresses. Ramona endures some embarrassing episodes at school and learns to address a misunderstanding she has with her teacher. At home, Ramona observes the strain that financial concerns are placing on her family but affirms that they are still a happy family.

The story is told from Ramona's point of view, with sympathy for the confusion she sometimes experiences when she does not fully understand what she sees and hears. The author also acknowledges that events that might seem trivial to an adult may be extremely important to a child. When Ramona's mother mistakenly puts a raw egg in her lunch box instead of the hard-boiled egg she is expecting, Ramona ends up with egg in her hair from cracking the shell on her head. She overhears her teacher say "What a nuisance", and mistakenly believes the remark to be about her personally.

Ramona spends the next several weeks of school trying not to be a nuisance to her teacher. The result is that when she is truly sick one day she puts off saying anything until it is too late and she throws up in class, causing her further embarrassment. In the end, Ramona gathers the courage to talk to her teacher about the remark and learns that it was not about her, but about the nuisance of getting egg out of hair.

On her first day, Ramona is teased by a boy in her class. She stands up to the boy and responds with some remarks of her own. She soon comes to feel that the boy possibly likes her and realizes she likes him, as well.

At home, Ramona's father has quit his full time job to return to school and her mother has taken a job. After school, she goes to a neighbor's house until her parents come home, which is a new experience for her, and she resents being expected to play with much younger children. Her parents are watching their money closely and Ramona notices that they are eating less expensive foods and that she and her sister are asked to share in more housekeeping chores. She observes her parents' concern when their car needs a major repair. She shares in their worries even though she does not completely understand them. The tension sometimes leads to quarreling among the family members, but the story ends on a positive note as they all enjoy a rare meal out at a restaurant and Ramona confirms that they are all happy together.