Utilizing national longitudinal data, this study examines how polygenic depression risk and childhood abuse interactively influence the life-course development of depressive conditions from middle to late adulthood. Data from 7512 participants (4323 females and 3189 males) of European ancestry aged 51–90, retrieved from the U.S. Health and Retirement Study (1992–2020), were analyzed. Childhood physical abuse and polygenic depression score were the primary predictors. Depressive symptoms were assessed using the Center for Epidemiologic Studies-Depression (CESD) scale, and clinical depression risk was a binary indicator. Growth-curve linear mixed and logit mixed-effects models were conducted for analysis. Increasing polygenic depression scores were associated with elevated CES-D levels and potential risks of clinical depression. Males experienced more detrimental effects of childhood abuse on depression development from ages 51 to 90 years. In contract, non-maltreated females generally exhibited higher depressive symptoms and clinical depression risk than males. A significant interactive effect was found between polygenic depression risk and childhood abuse among males. Higher depression levels and clinical risk were observed with increasing polygenic depression score among maltreated males, surpassing those of females with standardized polygenic score ≥0 from age 51 to 90 years. The interaction between childhood abuse and genetic factors significantly shaped lifelong depression trajectories in males, while the negative impact of abusive parenting remained constant regardless of polygenic depression risk among females. Individualized prevention and intervention strategies could be crucial in mitigating lifelong depression development, especially for high-genetic-risk males with a history of childhood physical abuse. •First study on childhood-abuse-genetic-risk interaction with lifelong depression.•Higher polygenic scores elevated depressive symptoms and clinical depression risk.•Childhood abuse worsened depression symptoms & clinical risk, especially in males.•Males with high genetic risk were more mentally harmed by childhood abuse.•Targeted interventions for high-risk males crucial to reduce lifelong depression.