"Mikadono San Shimai wa Angai, Choroi" centers on the life of Yuu, a high school student who unexpectedly becomes the caretaker of the three Mikadono sisters after their father, a wealthy businessman, passes away. The sisters—Miu, Niko, and Sara—are each distinct in personality and demeanor, creating a dynamic household filled with humor, tension, and occasional heartfelt moments. Miu, the eldest, is responsible and mature but struggles with her own insecurities. Niko, the middle sister, is cheerful and outgoing, often acting as the bridge between her siblings. Sara, the youngest, is quiet and reserved, harboring a deep sense of loss and vulnerability.

The narrative explores Yuu's adjustment to his new role as the sisters' guardian, balancing his responsibilities with his own personal growth. The series delves into themes of family, responsibility, and the complexities of relationships, as Yuu navigates the challenges of understanding and supporting each sister. The interactions between the characters are often lighthearted, with comedic moments arising from their contrasting personalities and the situations they find themselves in. However, the story also addresses deeper emotional undercurrents, particularly as the sisters confront their grief and learn to rely on one another.

As the series progresses, Yuu's presence becomes a stabilizing force for the Mikadono sisters, helping them heal and grow closer as a family. The plot avoids overly dramatic twists, instead focusing on the everyday struggles and triumphs of its characters, making it a grounded and relatable slice-of-life story. The relationships between Yuu and the sisters evolve naturally, with each episode contributing to their collective journey toward understanding and acceptance. The series balances its comedic and emotional elements, offering a well-rounded portrayal of familial bonds and personal resilience.