Background: Non-suicidal self-injury (NSSI) is a common harmful behavior during adolescence. Exposure to childhood family adversity (CFA) is associated with subsequent emergence of NSSI during adolescence. However, the pathways through which this early environmental risk may operate are not clear. Aims: We tested four alternative hypotheses to explain the association between CFA and adolescent-onset NSSI. Methods: A community sample of n = 933 fourteen year olds with no history of NSSI were followed for three years. Results: Poor family functioning at age 14 mediated the association between CFA before age 5 and subsequent onset of NSSI between 14-17 years. Conclusion: The findings support the cumulative suboptimal environmental hazards (proximal family relationships as a mediator) hypothesis. Improving the family environment at age 14 may mitigate the effects of CFA on adolescent onset of NSSI.