This study examined the program effectiveness of Health Rocks!, a youth substance use prevention program. Merging data from 128,544 youth participants in 21 states between 2009 and 2021, this study compared self-reported levels of knowledge, skills, and internal and external assets before and after the program. Youth reported significant increases in substance use knowledge, stress-coping skills, and assets to make healthy life decisions across eleven years. The magnitude of effects varied by individual characteristics, including gender, school grade level, race, ethnicity, and residence. We provide recommendations for the evaluation of substance use prevention program effectiveness.