Preparing for the Drug Free Years (PDFY) is a preventive intervention that targets parenting behaviors, family interaction patterns, and adolescent substance use, factors that have been shown to predict depression among teenagers. Effects of PDFY on trajectories of self-reported adolescent depressive symptoms from 6th through 12th grade were examined. Latent growth curve modeling was used to analyze data from 429 rural adolescents from schools assigned randomly to an intervention or a control condition. PDFY reduced the rate of increase in depressive symptoms during adolescence. Mediation of the intervention effect on depressive symptoms through reduced polysubstance use was tested; the indirect effect was only marginally significant. Findings have implications for understanding the relationship between adolescent depressive symptoms and substance use, and for preventing these outcomes.