Adolescence is a key developmental period for preventing substance use initiation, however prevention programs solely providing educational information about the dangers of substance use rarely change adolescent substance use behaviors. Recent research suggests that mind-body practices such as yoga may have beneficial effects on several substance use risk factors, and that these practices may serve as promising interventions for preventing adolescent substance use. The primary aim of the present study was to test the efficacy of yoga for reducing substance use risk factors during early adolescence. Seventh-grade students in a public school were randomly assigned by classroom to receive either a 32-session yoga intervention (n = 117) in place of their regular physical education classes or to continue with physical-education-as-usual (n = 94). Participants (63.2 % female; 53.6 % White) completed pre- and post-intervention questionnaires assessing emotional self-regulation, perceived stress, mood impairment, impulsivity, substance use willingness, and actual substance use. Participants also completed questionnaires at 6-months and 1-year post-intervention. Results revealed that participants in the control condition were significantly more willing to try smoking cigarettes immediately post-intervention than participants in the yoga condition. Immediate pre- to post-intervention differences did not emerge for the remaining outcomes. However, long-term follow-up analyses revealed a pattern of delayed effects in which females in the yoga condition, and males in the control condition, demonstrated improvements in emotional self-control. The findings suggest that school-based yoga may have beneficial effects with regard to preventing males' and females' willingness to smoke cigarettes, as well as improving emotional self-control in females. However additional research is required, particularly with regard to the potential long-term effects of mind-body interventions in school settings. The present study contributes to the literature on adolescence by examining school-based yoga as a novel prevention program for substance use risk factors.