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Background: There are multiple risk factors during adolescence, which become precursors of various diseases and injuries inflicting high morbidity, mortality, and disability. There are several gaps in adolescent health research in India; one among them is that programs targeting adolescent health are constrained by the absence of rigorous interventional research informing interventions for improving adolescent health. This study aims to document the effectiveness of intervention on adolescent health and knowledge change on the risk factors among adolescents in one of the selected districts in Gujarat, India. Methods: This was an interventional study with quasi-experimental design executed in one of the blocks of Gujarat. Baseline was conducted in 2013-2014 followed by intervention and the end line during 2016-2017. A structured validated questionnaire after pilot testing was executed to collect information on sociodemographic profile, nutrition status, menstrual hygiene practices, reproductive and sexual health, substance abuse, program awareness and utilization, and empowerment through life skills of adolescents in baseline and end line survey. Data analysis was carried out using IBM SPSS Statistics for Windows, Version 20.0. (Armonk, NY: IBM Corp). Results: This study documented increased awareness regarding anemia, knowledge about STD and HIV/AIDS, reduced addiction to tobacco, improved practices during menstrual hygiene and engagement with adolescent services/schemes in the intervention site. Conclusion: This study concludes that evidence-based interventions lead to increase in knowledge and practices; however, some improvements have also been documented in the nonintervention site. Therefore, changes due to interventions could not be attributed completely for improving adolescent health. Further long term interventional studies are required to develop a robust evidence on improving health of adolescents in India. [ABSTRACT FROM AUTHOR]