Adolescence is a critical period for intervention with at-risk youth to promote emotional well-being, deter problematic behavior, and prevent the onset of lifelong challenges. Despite preliminary evidence supporting mindfulness interventions for at-risk youth, few studies have included implementation details or reported feasibility and acceptance in ethnically diverse at-risk adolescents in a school setting. We conducted a randomized pilot study of a school-based mindfulness program, Learning to BREATHE, with ethnically diverse at-risk adolescents. Twenty-seven students were randomly assigned to a mindfulness or substance abuse control class that occurred for 50 min, once a week, over one school semester. Adjustments were made to increase acceptability of the mindfulness class, including enhanced instructor engagement in school activities. Reductions in depression were seen for students in the mindfulness class compared to controls. Initially, students’ perceived credibility of the mindfulness class was lower than that of the substance abuse class. Over the semester, perceived credibility of the mindfulness class increased while that of the substance abuse class decreased. Qualitative acceptability measures revealed that the mindfulness class helped to relieve stress and that students favored continuing the class. This study provides practical knowledge about what works with this unique population in a school setting and offers suggestions for future studies.