Chronic stress is associated with dysregulations in the physiological stress system, resulting in diverse negative developmental outcomes. Since adolescence is a period characterized by increased stress-sensitivity, and schools are an important environment for the developing adolescent, school-based interventions promoting psychosocial functioning are of particular interest to prevent adverse outcomes. The present study therefore aimed to investigate the effectiveness of such interventions on hypothalamic pituitary adrenal-axis (i.e., cortisol) and cardiovascular (i.e., blood pressure [BP] and heart rate [HR]/heart rate variability [HRV]) parameters of stress in adolescents, and examined moderators of effectiveness. The search resulted in the inclusion of k = 9 studies for cortisol, k = 16 studies for BP, and k = 20 studies for HR/HRV. The results indicated a significant small overall effect on reducing BP, but no significant effect for HR/HRV. For cortisol, large methodological variation in the few primary studies did not allow for quantitative analyses, but a qualitative review demonstrated inconsistent results. For BP and HR/HRV, larger effects were observed for intervention programs with a mindfulness and/or meditation component, for interventions without a cognitive-behavioural component and for interventions with a higher intensity. Providing adolescents with techniques to improve indicators of physiological stress may prevent emerging mental health problems.