BACKGROUND: This systematic review synthesizes evidence from 10 intervention studies focused on substance use interventions for adolescents across eight South Asian countries. METHODS: A literature search was conducted across MEDLINE (Ovid), Embase (Ovid), PsycINFO (EBSCO), Global Index Medicus, Web of Science (Clarivate), and Global Health (CAB Direct), covering studies from database October 1, 2016 to May 28, 2024. Only randomized control trials and quasi-experimental designs were included. The search strategy was pre-registered on the Open Science Framework. RESULTS: Out of 6356 studies identified, 4494 were screened, 193 were assessed for eligibility, and 10 studies were included in the review after consensus by two independent reviewers. Across these studies, which included 16,241 participants aged 9-18, seven were universal interventions, while three were targeted toward adolescents who were already using substances. Interventions primarily were conducted in school settings (n = 8) with a focus on tobacco, alcohol, inhalants, and supari use. Most studies demonstrated low selection and reporting bias, though performance and detection bias were unclear due to blinding limitations. Intervention duration ranged from 2 to 24 weeks and included between 2 and 119 sessions. Effectiveness was noted in four studies, three had mixed outcomes, two reported no significant effects, and one showed effects opposite of predicted outcomes. CONCLUSION: This review reveals varied intervention outcomes on adolescent substance use in South Asia, with positive effects in a subset of studies. These findings highlight the need for additional interventions with strong methodological rigor to reduce adolescent substance use and misuse in this region.