Ramona Quimby (JOEY KING) is a 9-year-old girl whose overactive imagination often amuses her parents, Robert (JOHN CORBETT) and Dorothy (BRIDGET MOYNAHAN), but also means that she doesn't live up to the personal and school standards set by her "perfect" teenage sister, Beezus (SELENA GOMEZ).
The latter is near constantly irritated by her younger sister (including her nickname that stemmed from Ramona being unable to pronounce Beatrice when she first learned to talk), and Ramona often feels inadequate and inferior compared to Beezus who's developing romantic feeling for her longtime friend, Henry (HUTCH DANO).
While Ramona has a good friend in Howie (JASON SPEVACK), it doesn't help that classmate Susan (SIERRA McCORMICK) is always putting her down or that their teacher, Mrs. Meacham (SANDRA OH), is disappointed in her performance at school. She does get support from her Aunt Bea (GINNIFER GOODWIN), but she's recently been distracted by Howie's uncle, Hobart (JOSH DUHAMEL), her former high school sweetheart who wants to win her back despite him preparing to move to Alaska.
When her dad loses his job and her mom has to go back to work, Ramona's worries intensify, be that her parents will get divorced or that the family will lose their house. As everyone tries to cope with those and other developments, Ramona tries to sort through everything, all while Beezus' constant irritation toward her younger sibling is tempered by her deep-down love for her.