Increased levels of psychological stress during adolescence have been associated with a decline in academic performance, school dropout and increased risk of mental health problems. Intervening during this developmental period may prevent these problems. The school environment seems particularly suitable for interventions and over the past decade, various school-based stress reduction programs have been developed. The present study aims to evaluate the results of (quasi-)experimental studies on the effectiveness of school-based intervention programs targeting adolescent psychological stress and to investigate moderators of effectiveness. A three-level random effects meta-analytic model was conducted. The search resulted in the inclusion of k = 54 studies, reporting on analyses in 61 independent samples, yielding 123 effect sizes (N = 16,475 individuals). The results indicated a moderate overall effect on psychological stress. Yet, significant effects were only found in selected student samples. School-based intervention programs targeting selected adolescents have the potential to reduce psychological stress. Recommendations for practice, policy and future research are discussed.