--- - |2+ Objective Lifestyle variables such as drug use and excessive weight gain contribute to adult morbidity and mortality. This study was designed to determine whether participation in a preventive intervention designed to enhance supportive parenting can reduce drug use and body mass index (BMI) in young Black adults from disadvantaged neighborhoods. Method This study was conducted in the rural southeastern United States. Black parents and their 11‐year‐old children (517 families) were assigned randomly to the Strong African American Families (SAAF) prevention trial or a control condition. Data assessing neighborhood socioeconomic status and supportive parenting were obtained when the youths were ages 11 and 16. When youths were ages 19–21 and 25, drug use and BMI were measured. Results As hypothesized, significant three‐way interactions were detected among neighborhood disadvantage, prevention condition, and gender for BMI (B = 3.341, p = .009, 95% CI [0.832, 5.849]) and substance use (B = −0.169, p = .049, 95% CI [−0.337, −0.001]). Living in a disadvantaged neighborhood during adolescence was associated with increased drug use among young men in the control group (simple‐slope = 0.215, p < .003) but not among those in the SAAF condition (simple‐slope = 0.030, p = .650). Neighborhood disadvantage was associated with elevated BMI among young women in the control group (simple‐slope = 3.343, p < .001), but not in the SAAF condition (simple‐slope = 0.204, p = .820). Conclusions The results suggest that participation during childhood in a preventive intervention to enhance supportive parenting can ameliorate the effects of life in a disadvantaged neighborhood on men's drug use and women's BMI across ages 19–25 years. These findings suggest a possible role for parenting enhancement programs in narrowing health disparities. - Journal of Child Psychology and Psychiatry, EarlyView.