Background: Schools are considered natural environments in which to enhance students’ social–emotional skills and mental health in general, but they can be especially important for students with refugee and immigrant backgrounds. The current study tested the effectiveness of two school-based interventions in enhancing the mental health and wellbeing of adolescents of native, refugee, and immigrant backgrounds. It further analyzed the role of age, gender, daily stressors, and discrimination in affecting the interventions’ effectiveness. Methods: A three-arm cluster RCT with parallel assignment was applied among the 16 schools. Schools were randomized to three conditions of two active interventions and a waiting-list control condition. Students (n = 1974) filled in an online questionnaire at baseline before the interventions, after the interventions, and at follow-up an average of 9 months after the interventions. The effectiveness criteria were internalizing and externalizing problems, resilience, and prosocial behavior. Results: Interventions were generally not effective in decreasing mental health problems and increasing psychosocial resources. The expected positive intervention effects were dependent on students’ age and gender and exposure to socioeconomic daily stressors. Conclusion: Interventions enhancing teacher awareness and peer relationships at school should be carefully tailored according to the strengths and vulnerabilities of participating students, especially their daily stress exposure, but also age and gender.