Sakura's childhood was defined by severe illness and isolation. Born with a weak constitution, she suffered from ailments caused by evil spirits inhabiting her body, preventing interaction with other children. Her uncle, the Buddhist monk Cherry, cared for her during this lonely period. A significant childhood event occurred when hiding in a closet triggered her ability to see spirits and ghosts. Later, in middle or high school, she briefly dated a boy who biked her home daily, until he began seeing another girl.

A pivotal encounter happened outside a ramen shop, colliding with Ataru Moroboshi. Sensing the evil spirits within him, Sakura offered purification. Her true intent, however, was to transfer the spirits attached to her own illnesses into Ataru. This act succeeded, curing her ailments and granting her permanent health. Following this, she joined Tomobiki High School as the school nurse while continuing her work as a Shinto priestess, often collaborating with Cherry to exorcise spirits plaguing the town.

Tall, slender, and conventionally attractive, Sakura's beauty contrasts sharply with her mother and uncle Cherry's similar appearances. This makes her the object of affection for male students and staff like Onsen-Mark, prompting students to intentionally injure themselves to visit the infirmary. Despite her refined looks, she speaks and behaves in an old-fashioned manner. She shares Cherry's enormous appetite, consuming vast quantities without weight gain, often humorously dismissing concerns by claiming to be "on a diet." Her exorcism chant, "Haratama! Kiyotama!" translates to "Exorcise! Purify!" She exhibits coldness and violent reactions when angered or harassed, particularly by Ataru's advances, though she occasionally displays subtle care for those in genuine distress.

Her relationships are complex. She maintains familial ties with Cherry, allowing him to live in her home and conduct experiments in her office despite frequent clashes over his gluttony and habits. She harbors deep animosity toward Ataru due to his constant flirtation and the spirits she transferred, often reacting with physical violence. She is engaged to Tsubame Ozuno, a sorcerer who studied in the West, though their relationship faces frequent interruptions from Ataru and others. Ten, Lum's young cousin, developed romantic feelings, leading to a single date ending in rejection due to his age, though he retains lingering affection.

Sakura possesses significant spiritual abilities. She exorcises and purifies demons and spirits, a skill frequently employed in Tomobiki. She also demonstrates the rare capacity to summon spirits. Physically, she exhibits superhuman strength, particularly when enraged, often demonstrated repelling Ataru violently. Her most distinctive trait is a perpetual appetite, eating endlessly without weight gain – once bankrupting an all-you-can-eat restaurant and leading to an eating contest against the Fast-Food Fighters at Mendō's supermarket.

Most characters address her formally: Ataru uses "Sakura-san," Lum uses "Sakura," and students like Shinobu use "Sakura-sensei." In return, she uses last names like "Moroboshi" for Ataru and "Mendō" for Shūtarō Mendō, reflecting her traditional demeanor. Her fiancé Tsubame uses "Sakura," while she calls him "Tsubame." She refers to Ten by his name and addresses her uncle Cherry with the formal "Oji-ue."