Evidence suggests that the consequences of chronic exposure to stressors extend beyond psychological effects, and that adolescents living in socio-economically disadvantaged neighborhoods may experience an accumulation of exposure to stressors that wears down the physical systems in the body, resulting in hyper-activation of the stress response. This research examines the relationship between exposure to neighborhood stressors and salivary cortisol reactivity in a sample of 163 at-risk African American adolescents (average age 21; 50% female) living in disadvantaged urban neighborhoods. More specifically, the relationship between neighborhood stressors and physiological stress, measured by baseline cortisol and cortisol reactivity is assessed. This research also examines several moderating pathways between exposure to neighborhood disadvantage and cortisol reactivity including substance use, high effort coping, psychological stress and social support. Results indicate that both individual and neighborhood-level factors influence adolescent cortisol. High effort coping and psychological stress were associated with cortisol in the sample, and exposure to neighborhood socio-economic disadvantage resulted in an atypical cortisol response. In addition, neighborhood disadvantage interacted with intra- and interpersonal factors to affect cortisol indirectly. Thus, living in disadvantaged neighborhoods may take a psychological and physiological toll on adolescents, and it also may exert synergistic effects through individual coping and vulnerabilities.