This study provides insights into the roles played by perceived stress and social support in the relationship between cumulative risk exposure (CRE) and adolescent emotional distress. Preregistered longitudinal moderated mediation analyses were used to test hypotheses relating to the association between CRE and later emotional distress; the mediating role of perceived stress in the relationship between CRE and later emotional distress; and, the moderating effects of peer and adult-level family support on the relationship between CRE and later perceived stress, among N = 19,159 adolescents over three annual waves (at ages 11/12, 12/13, 13/14). Analyses revealed that CRE significantly predicted later adolescent emotional distress. This relationship was partially mediated by perceived stress. Both peer and adult-level family support significantly moderated the impact of CRE on later perceived stress (i.e., adolescents reporting higher levels of support perceived significantly lower levels of stress resulting from CRE compared to those reporting lower levels of support). These findings provide critical empirical evidence of the roles played by perceived stress and social support in the relationship between CRE and adolescent emotional distress, with consequent implications for intervention.