Background: We evaluated the 12-month effects of the COPE (Creating Opportunities for Personal Empowerment) Healthy Lifestyles TEEN (Thinking, Emotions, Exercise, Nutrition) program versus an attention control program (Healthy Teens) on overweight/obesity and depressive symptoms in high school adolescents. Methods: A cluster randomized controlled trial was conducted. Participants were 779 culturally diverse adolescents in the US Southwest. COPE is a cognitive-behavioral skills-building intervention with 20?min of physical activity integrated into a health course and taught by teachers once a week for 15 weeks. Outcome measures included body mass index (BMI) and depressive symptoms. Results: COPE teens had a significantly lower BMI at 12?months (F[subscript 1,698]?=?11.22, p?=?0.001) than Healthy Teens (24.95 versus 25.48). There was a significant decrease in the proportion of overweight and obese COPE teens from baseline to 12 months (?[superscript 2]?=?5.40, p?=?0.02) as compared with Healthy Teens. For youth who began the study with extremely elevated depressive symptoms, COPE teens had significantly lower depression at 12 months compared with Healthy Teens (COPE M?=?42.39; Healthy Teens M?=?57.90); (F[subscript 1,12]?=?5.78, p?=?0.03). Conclusions: COPE can improve long-term physical and mental health outcomes in teens.