The health impacts of smoking and alcohol abuse have been long established with smoking representing one of the most preventable causes of disease and alcohol use the most popular psychoactive substance among adolescents. The current study evaluated stage of change progression in a large (N = 4,158) school-based, computer-delivered, transtheoretical model (TTM)-tailored multiple behavior intervention focused on preventing acquisition of smoking and alcohol use in adolescents. Assessments began in sixth grade and continued yearly until eighth grade, with a follow-up in ninth grade. Markov modeling was used to (a) characterize the best pattern of stage movement (e.g., no stage change, stage-sequential change, stages skipped), (b) test whether the identified pattern was stable over time (e.g., between assessments and after intervention completion), and (c) to determine whether the substance use prevention (SP) intervention effectively kept adolescents in acquisition stages (e.g., prevents stage movement toward substance use), relative to the comparison intervention. Major findings supported positive effects for both the intervention and comparison condition, which focused on energy balance (EB) behaviors and provided no direct intervention on substance use behaviors. Substantial differences in stage membership and transitions across intervention conditions highlighted the process of smoking and alcohol use acquisition in middle school students across each intervention condition.