Upon enrolling in Seiran Academy, Nanako Misonoo hopes for a promising future. Sadly, she's exposed to a world riddled with lies, sorrow, and envy. Moreover, the school's popular clique, the Sorority, picks Nanako to become their newest member, drawing animosity from her peers due to her lack of poise, riches, and skills - particularly from Aya Misaki. To deal with the school's mounting atrocities, Nanako confides in her former mentor, Instructor Takehiko Henmi, fondly referred to as "onii-sama" (big brother), through the letters she writes. Her four closest allies - childhood chum Tomoko Arikura, sociable yet unpredictable Mariko Shinobu, troubled musician Rei Asaka, and athletic tomboy Kaoru Orihara - also offer solace amidst her troubles. Oniisama e... presents an impassioned narrative about the cruelty of bullying as it tells the harsh story of a young woman at her new school, subjected to malicious rumors, hostile classmates, and various social challenges.