Ramona Quimby is a spirited third-grader with an overactive imagination, which often gets her into trouble. Living with her older sister Beezus, played by Selena Gomez, and their parents, Ramona continually finds herself at the heart of chaotic yet endearing mishaps. Despite her good intentions, her whimsical schemes frequently spiral out of control, much to the exasperation and amusement of her family and friends. Beezus, who is more mature and responsible, often finds herself at odds with Ramona's antics but also deeply cares for her younger sister.

As the family faces financial difficulties, their father loses his job, putting additional strain on everyone. Ramona takes it upon herself to help, concocting ambitious plans to contribute money to her family and save their home. Meanwhile, Beezus navigates her own coming-of-age challenges, including her first crush and the pressures of high school. Throughout their ups and downs, the sisters discover the strength of their bond, learning important lessons about family, love, and resilience. Ramona's imaginative adventures and heartfelt determination ultimately highlight the importance of creativity and perseverance in overcoming life's obstacles.