Relapse cases among mentally ill patients are a significant public health concern, with an estimated 1 in 8 people experiencing mental disorders each year. It is on this basis that this study examined family support and self-esteem as predictors of relapse among mentally ill patients in Kaduna Metropolis, Nigeria. A cross-sectional survey design was employed where a total of 90 participants comprising of (76 male and 14 females) with age ranging from 16 to 70 years participated in the study. Purposive sampling technique was used to select patients receiving care at the 44 Nigerian Army Reference Hospital Kaduna and the Federal Neuropsychiatric Hospital Kaduna. Data was collected using standardized questionnaire comprising of the Index of Family Relations (IFR), the Rosenberg Self-Esteem Scale (RSES), and the Management of Early Warning Signs of Relapse Questionnaire (MEWSReQ). Data was analyzed using descriptive and inferential statistics such as Pearson correlation, independent samples t-test, and multiple regression analysis. Three hypotheses were tested and result of hypothesis one indicated no statistical significant difference in relapse between soldiers (M = 39.22) and civilian patients (M = 38.47), (t[88] = −0.47, p = .642). Result of hypothesis two showed that family support did not significantly predict relapse (β = .025, p = .811). Result of hypothesis three showed that self-esteem significantly predicted relapse positively (β = .396, p < .001) with lower self-esteem associated with higher relapse risk. Result of hypothesis four showed that family support and self-esteem significantly predicted relapse (F(2, 87) = 8.574, p < .001); the two predictors accounted for approximately 16.5% of the variance in relapse scores. The researcher concluded that self-esteem is a critical psychosocial determinant of relapse in this population. It is recommended that mental health facilities in Kaduna incorporate a structured self-esteem intervention into routine treatment of all patients with mental illness.