Prenatal drug exposure (PDE) can undermine subsequent health and development. In a prospective longitudinal study we examine whether PDE moderates the link between stress reactivity and cognitive functioning in adolescence. Participants were 76 prenatally drug-exposed and 61 nonexposed (NE) community comparison African American youth (50% male, mean age 14.17 years) living in an urban setting. All participants completed neuropsychological and academic achievement tests (Children's Memory Scales, the California Verbal Learning Test - Children's version and the Wide Range Achievement Test 4) over the course of 1 day in a laboratory setting. Two mild stressors (Balloon Analog Risk Task - Youth and Behavioral Indicator of Resilience to Distress) were administered, with saliva samples (assayed for cortisol) collected pre- and poststress task. A higher percentage in the NE group, compared to the PDE group (26% vs. 12%, χ(2) = 4.70, d.f. = 1, n = 137, p = 0.03), exhibited task-related increases in salivary cortisol. PDE moderated the association between stress reactivity and 11 of 15 cognitive performance scales. In each case, the NE stress reactive group had better cognitive performance than either the NE lower cortisol reactive group or the PDE group regardless of stress reactivity status. Stress-related reactivity and regulation of the hypothalamic-pituitary-adrenal axis in adolescence may be disrupted by PDE, and the disruption may be linked to lower cognitive performance.