The aim in the current study was to investigate the effectiveness of an online, self-directed cognitive-behavioral therapy program (MoodGYM) in preventing and reducing the symptoms of anxiety and depression in an adolescent school-based population. A cluster randomized controlled trial was conducted with 30 schools (N = 1,477) from across Australia, with each school randomly allocated to the intervention or wait-list control condition. At postintervention and 6-month follow-up, participants in the intervention condition had significantly lower levels of anxiety than did participants in the wait-list control condition (Cohen's d = 0.15-0.25). The effects of the MoodGYM program on depressive symptoms were less strong, with only male participants in the intervention condition exhibiting significant reductions in depressive symptoms at postintervention and 6-month follow-up (Cohen's d = 0.27-0.43). Although small to moderate, the effects obtained in the current study provide support for the utility of universal prevention programs in schools. The effectiveness of booster sessions should be explored in future research.