Canada is in the midst of an ongoing, escalating opioid crisis, with significant impacts on adolescents and young adults. Accordingly, mental health impairment was examined as a risk factor for non-medical prescription opioid use (NMPOU) among high school students. In addition, the moderating effects of the school environment, in terms of the availability of mental health services and substance use policies, were characterized. Self-reported, cross-sectional data were obtained from the COMPASS study, including 61,239 students (grades 9–12) in 121 secondary schools across Canada. Current and lifetime NMPOU were ascertained. Categorical indicators of mental health impairment and school environment were derived. The main analytical strategy encompassed hierarchal multilevel logistic regression, including the addition of interaction terms to characterize the moderation effects. Current and lifetime NMPOU were reported by 5.8% and 7.2% of the students, respectively. After adjusting for confounders, students in the highest quintile of mental health impairment had odds ratios (OR) of 2.60 (95% confidence interval [CI] 2.29–2.95) and 2.96 (95% CI 2.64–3.33) for current and lifetime NMPOU, respectively when compared to students in the lowest quintile of mental health impairment. A significant interaction between mental health impairment and school environment indicated relatively lower risks of NMPOU in students from schools that provide more mental health services and have stricter substance use policies. Mental health impairment increased the risk of NMPOU, but the associations were moderated by the school environment. These findings underscore the importance of mental health services and substance use regulations in schools.