Background: Tobacco users disproportionately reside in lower-and-middle income countries, with many people beginning consumption of tobacco in adolescence. Countries employ interventions in schools as a means of providing health education thereby creating mass awareness among them. However, research has mostly restricted to developed nations. Objective: To examine the impact of interventions implemented in preventing tobacco uptake among adolescents in school setting in South-East Asia region. Method: The protocol was registered prospectively on PROSPERO (CRD42022337341). Systematic search was conducted on 6 databases: PubMed, Embase, Scopus, CINAHL, ProQuest and Web of Science. Randomized Control Trials (RCT) and Cluster RCT conducted in school set-up in South-East Asia among adolescents below 18 years' age were included. Articles between timeline 2002-2022 were considered. Results: From a total of 963 articles, total of 13 studies were included. Four were RCT, while nine were Cluster RCT. Most of the studies were targeted at change in prevalence, followed change in knowledge and attitude towards tobacco and impact on susceptibility to use tobacco. Nine studies had interventions based on Health Promoting School Framework, three were Peer-led Interventions and one was Counsellor-centred Intervention. Risk of Bias assessment revealed eight studies had low risk of bias, two had some concerns while three were high risk studies. Conclusion: Interventions that focus on building a holistic environment and go beyond the usual classroom environment have primarily been implemented and found to be effective in this region. There is a need for strong, high-quality RCT studies with standardised evaluation techniques to combat tobacco use among adolescents.