Obesity in adolescence is associated with stigma during school years, early emergence of co-morbidities in adulthood and premature mortality. Adolescence presents a key window of opportunity to intervene for building healthy eating and physical activity routines and prevent weight gain. This review of reviews assesses the evidence on the effectiveness of prevention interventions conducted with adolescents. Nine reviews assessing the effects of lifestyle interventions in adolescents (defined as age 10 to 19 years old) on weight gain were identified from the 10 health databases searched. Only four reviews conducted meta-analyses, of which, three (two exercise-focused) demonstrated positive changes in primary outcomes of body mass index (BMI) and/or BMI z-score (range of decrease in BMI from 0.06 to 0.47 kg/m2)). Most were conducted in school settings, and all but two reviews were of low quality. Few reviews reported external validity components that would enable clearer directions for policy makers to implement in real-world settings. More than 140 distinct interventions were included in the reviews, but there remains a serious gap in evidence for effective interventions in adolescents.