This paper presents a systematic review on the effectiveness of prevention, early intervention, and harm reduction including treatment of substance abuse among adolescents for tobacco, alcohol and illicit drugs. Taxation, public consumption bans, restriction on advertisements, and minimum legal age for consumption, are effective measures to reduce the use of tobacco and alcohol. School-based prevention and skill-training interventions are effective tools to reduce substance use among adolescents. Social norms and intervention to reduce substance use in adolescents do not have strong evidence of effectiveness. Road-side testing and reduction of injection related harm are effective. However, further research is needed to support it. Moreover, the available research evidence comes from the Western countries with questionable applicability in Indian setting. Research is needed to increase the evidence base on interventions that aim to reduce the high burden of substance use in adolescents in India.