Adolescents present high risk of developing mental health problems. Different school-based programs have been designed to prevent and treat the psychological distress that they often experience with disparate results. In this study, we tested the efficacy of a school-based program framed into the "Escuelas Despiertas" initiative that teaches adolescents mindfulness and compassion to improve their mental health. In this randomized controlled trial, high school students from four Spanish secondary education centers (N = 277) were randomly assigned to a school-based 10-session mindfulness and compassion program ("Escuelas Despiertas") or a relaxation program. Participants were assessed at baseline, posttreatment, and at 6-month follow-up. The main outcome was psychological distress (General Health Questionnaire, GHQ-12). Classroom climate and relaxation habits, among others, were assessed as secondary outcomes. Students who underwent the "Escuelas Despiertas" program experienced small within group improvements posttreatment in GHQ-12 scores (p = 0.001, d = 0.31) and in relaxation habits (p = 0.001, d = 0.35), although these were not significant compared to the control group. Classroom climate presented a small deterioration in the "Escuelas Despiertas" group compared to the relaxation group in the follow-up assessment, but this effect was not statistically significant after correcting for multiple comparisons. In conclusion, the "Escuelas Despiertas" program produced small short-term improvements in psychological distress and relaxation habits in adolescents which were not significant compared to a relaxation intervention. In line with previous studies, it seems that punctual interventions delivered during some weeks might not be the best approach for adolescents, for whom mindfulness- and-compassion-based programs may not be engaging enough for different reasons.