This study evaluated emerging adult effects of the PROmoting School-Community-University Partnerships to Enhance Resilience (PROSPER) universal prevention delivery system implemented in middle schools. Twenty-eight rural school districts were randomized to intervention and control conditions, with 1985 nineteen-year-old participants (90.6% White, 54.1% female) evaluated through age 25. Intent-to-treat, multi-level, point-in-time analyses of covariance and growth analyses were conducted. Outcomes were assessed with self-report measures of substance misuse (lifetime, current, frequency) and conduct problem behaviors. Analyses showed very limited point-in-time effects; there were growth pattern effects on measures of illicit drugs, non-prescribed drugs, cigarettes, and drug problems. When risk moderation was observed, it favored higher-risk participants. These emerging adult effects concerning slower growth of lifetime misuse combine with more robust adolescent stage findings to support PROSPER's public health value.