Leprosy has long-term consequences related to impairment and stigma. This includes a major impact on mental health. This study aims to consolidate current evidence regarding the mental health impact of leprosy on affected persons and their family members. In addition, determinants influencing mental health outcomes among leprosy-affected persons and effective interventions are examined. A keyword-based search was conducted in PubMed, Web of Science, Scopus, PsycINFO, Infolep and InfoNTD; additional literature was also considered. Articles presenting primary data involving leprosy-affected persons or their family members experiencing mental conditions were included. Independent extraction of articles was executed using predefined data fields. Articles were sorted according to relevance. In total, 65 studies were included in this systematic review. Multiple psychiatric morbidities have been identified among leprosy-affected persons, including depression, anxiety disorders and suicide (attempts). Additional factors were found that may impact mental health. Moreover, studies found that demographic factors, lifestyle and disease-specific factors and stigma and discrimination impact mental health. Depressive symptoms and low self-esteem were identified among children of leprosy-affected persons. In addition, interventions were identified that could improve the mental wellbeing of leprosy patients. Depressive disorders and anxiety disorders were found to be very common among persons affected by leprosy. Feelings such as fear, shame and low self-esteem are also experienced by those affected, and their children. Further research is necessary to ensure that mental health impact is included when determining the burden of disease for leprosy, and to relieve this burden.