Although uterine leiomyomas are the most common benign uterine tumors in women, there is no effective therapy that can also preserve the uterus and maintain fertility. The work aimed to work was to discover a potential natural agent that has pharmacological activities on uterine leiomyomas with fewer adverse effects. We chose Rhus verniciflua Stokes (RVS) as a candidate after primary cytotoxicity testing, and analyzed the RVS components that showed pharmacological activity. Leiomyoma cells and myometrium cells were cultured from uterine tissues obtained from patients, and were treated with RVS at varying concentrations. RVS was cytotoxic in both leiomyoma and myometrium cells; however, the effects were more prominent in the leiomyoma cells. Among the bioactive components of RVS, fisetin showed significant pharmacological effects on leiomyoma cells. Fisetin showed excellent leiomyoma cell cytotoxicity and induced apoptotic cell death with cell cycle arrest. The apoptotic cell death appeared to involve not one specific pathway but multichannel pathways (intrinsic, extrinsic, MARK, and p53-mediated pathways), and autophagy. The multichannel apoptosis pathways were activated with a low concentration of fisetin (<IC20) and were more vigorously activated at high concentrations (>IC50). This is the first demonstration to show the pharmacological activities of fisetin on leiomyoma cells. These findings suggest that fisetin may be used for the prevention and treatment of uterine leiomyomas. Since fisetin can be obtained from plants, it may be a safe and effective alternative treatment for uterine leiomyomas.