Past research has demonstrated the particularly damaging effects of exposure to multiple forms of victimization, or "poly-victimization," on youth mental health. The primary objective of the present study is to begin to identify the mechanisms that help explain its powerful impact. Analyses are based on two waves of longitudinal data from the National Survey of Children’s Exposure to Violence (NatSCEV), conducted in 2008 and 2010, that comprised a telephone sample of 1,186 youth ages 10 to 17. Using structural equation modeling, we examine direct and indirect effects on distress symptoms of increased, decreased, and stable high poly-victimization between Waves 1 and 2 compared to no or low victimization in both waves. Specifically, we consider the extent to which reductions in core psychosocial resources, including family support, peer support, self-esteem, and mastery, mediate the relationship between these poly-victimization conditions and distress. Relative to stable low victimization, both increased poly-victimization and stable high poly-victimization were associated with declines in all four resources. However, only self-esteem and mastery significantly mediated the association between poly-victimization and distress, with mastery showing the strongest effect. Although significant indirect effects were evident, poly-victimization still had a strong direct effect on distress with resource factors controlled. Findings support the hypothesis that the potent effect of poly-victimization on youth mental health is, in part, due to its damaging influence on core psychosocial resources.