Background: Breast cancer is a major global health concern, particularly in low-resource settings like Benin, where late-stage presentation often necessitates mastectomy. Mastectomy, while therapeutic, profoundly impacts body image, sexuality, and psychosocial well-being. However, evidence on these post-mastectomy outcomes is scarce in the Beninese context. This study aimed to assess the quality of life (QoL), psychosocial experience, and symptoms of anxiety and depression among mastectomized women in southern Benin.Methods: We conducted a descriptive and analytical cross-sectional study from August to December 2023 in two tertiary hospitals in Cotonou. A consecutive series of 42 women who had undergone total or partial mastectomy at least two months prior to inclusion were enrolled in the study. Data were collected using a structured questionnaire that included sociodemographic and clinical variables, the EORTC QLQ-C30 (global QoL), the EORTC QLQ-BR23 (breast cancer–specific domains), and the Hospital Anxiety and Depression Scale (HADS) for psychosocial assessment. Statistical significance was set at p < 0.05.Results: The 42 participants had a mean age of 55.4 years. Most had received chemotherapy (98%) and radiotherapy (79%). The mean global quality-of-life score (EORTC QLQ-C30) was 69.4, with generally high physical, emotional, cognitive, and social functioning scores. Sexual functioning and sexual satisfaction were the most impaired domains, while body image scores remained moderate. Only 2.3% of women presented clinically significant depressive symptoms on the HADS. Age, education level, income, and family support showed significant associations with several quality-of-life dimensions (p < 0.05).Conclusion: Despite socioeconomic constraints, mastectomized women in southern Benin reported overall satisfactory quality of life, although sexual functioning remained notably affected. These results underscore the critical need for integrated psychosocial and sexual support in survivorship care and provide initial evidence to inform patient-centred breast cancer care in Benin.