Purpose: To examine substance use differences among African‐American adolescents living in rural and more urban areas in Iowa and Georgia and factors thought to be related to those differences. Specifically, negative affect and perceived availability were examined as mediators of the relation between community size and alcohol, tobacco, and drug use. Methods: In‐home interviews with the adolescents (Time 1: N = 897, Mean age = 10.5) assessed their use, perceived substance availability, and negative affect across 3 waves. Their parents’ use was also assessed. Census data were used to determine community size (rural ≤ 2,500; urban ≥ 2,500). Findings: Perceived substance availability and use were both higher among the more urban adolescents. As expected, negative affect was a primary antecedent to use at each wave. Structural Equation Modeling indicated that the relation between population and use was mediated by perceived availability of the substances. Additional multigroup analyses indicated that the relations between negative affect and use were significantly stronger among the urban adolescents at all waves. Conclusions: Results suggest that stress or negative affect is an important antecedent to use among African‐American adolescents, especially when it occurs at an early age, but living in rural areas may be a buffer for both problems, in part, because exposure to this type of risk is lower in these environments.