Background: The goal of the current study was to evaluate the effects of the Social Emotional Learning program Skills 4 Life on mental health and its risk factors self-esteem, self-efficacy, and social interaction skills in students of secondary schools. Methods: A cluster randomized controlled study was conducted, including 38 schools (66 classes; grades 7 to 9) for secondary education, with a 1 year and 20 months follow-up (teachers and students reports). Results: The intervention was effective in improving self-efficacy, depressive symptoms, and teacher-reported psychological problem behavior, all after 20 months. Stratified analyses showed effects in mainly lower educational level students. Conclusion: The Skills 4 Life curriculum is effective in improving the mental health and self-efficacy among adolescents, especially for adolescents from lower educational level, a group that is most prone to ill mental health.