Young adolescents (N = 68) completed questionnaires concerning perceptions of neighborhood stress (i.e., high negative influences, low cohesion, and connectedness). Youth self-reported their own depressive symptoms and participated in a public speaking task designed to be moderately stressful. Increases in skin conductance in response to this laboratory-based challenge task were measured (i.e., skin conductance level reactivity; SCLR). Higher levels of depressive symptoms were associated with greater perceptions of neighborhood stress, with the effects of neighborhood stress particularly strong among boys. For boys only, the association between perceived neighborhood stress and depressive symptoms was moderated by SCLR. For boys with average or above average levels of SCLR, greater perceptions of neighborhood stress were associated with more depressive symptoms.