The present study evaluated a positive psychology school-based intervention aimed at enhancing mental health and empowering the entire educational staff and students at a large middle school in the center of Israel. 537 seventh- to ninth-grade students participated in a 1 year intervention program and were compared to 501 students in a demographically similar control school. In a 2-year longitudinal repeated measures design, the study assessed pre- to post-test modifications in psychological symptoms and distress and in targeted well-being factors that were promoted in the experimental but not in a wait list control condition. The findings showed significant decreases in general distress, anxiety and depression symptoms among the intervention participants, whereas symptoms in the control group increased significantly. In addition, the intervention strengthened self-esteem, self-efficacy and optimism, and reduced interpersonal sensitivity symptoms. These results demonstrate the potential benefits of evidence-based positive-psychology interventions for promoting school-children’s mental health, and point to the crucial need to make education for well-being an integral part of the school curriculum.