The study examined the efficacy of a school-based mindfulness intervention on mental health and emotion regulation outcomes among adolescents in a wait-list controlled trial. The study also explored mediators and moderators of intervention effects. A total of 145 predominantly ethnic minority (Asian and Latino) 9th grade students with elevated mood symptoms were randomized to receive a 12-week mindfulness intervention at the start of the academic year, or in the second semester of the year. Students completed measures of emotion regulation and mental health symptoms at baseline, post-intervention, and 3-month follow-up. Intent-to-treat analyses revealed significant treatment effects of the mindfulness intervention for internalizing symptoms and perceived stress at post-treatment. Pooled pre-to-post treatment analyses of the entire sample revealed a small effect size for attention problems, medium for internalizing and externalizing problems, and large for perceived stress. We also found a small effect size for cognitive reappraisal, medium for expressive suppression, emotional processing, emotional expression, and rumination and large for avoidance fusion. Mediation analyses showed that treatment effects on internalizing symptoms and perceived stress were mediated by reductions in expressive suppression and rumination. Moderation analyses revealed that treatment effects were larger among youth with more severe problems at baseline for internalizing problems, externalizing problems, and perceived stress. However, for attention problems, students with lower severity at baseline appeared to have larger treatment gains. The study provided evidence that mindfulness intervention was beneficial for low-income ethnic minority youth in reducing perceived stress and internalizing problems, and improving emotion regulation outcomes. Furthermore, mindfulness training was associated with reduced mental health symptoms via improvements in emotion regulation.