RationaleResilience prevents the emergence of stress-related mental health problems among adolescents. Adolescents in tribal areas of India are more prone to develop such problems. ObjectivesThe primary objective was to determine the effect of combined life skills-based health empowerment intervention on the resilience of school-going adolescents in a tribal area. The secondary objectives were to determine the effect of the intervention on internal health locus of control and self-determination and to compare the effect of intervention on resilience between non-tribal and tribal adolescents. MethodsWe conducted this quasi-experimental study using a Solomon four-group design among 742 adolescents in two schools of Purulia, West Bengal, India. Students of the pretested group were examined for resilience using the Child Youth Resilience Measurement scale. A life skills education-based health empowerment intervention was administered among students of the experimental group. Post-test data on resilience, self-determination, internal health locus of control and pathological behaviour was obtained 3 months after the completion of intervention. A multi-level general linear mixed model was constructed to determine the effect of intervention on resilience. ResultsResilience was less among tribal adolescents at baseline. The intervention significantly improved resilience [βAdjusted = 11.19 (95% CI = 10.55, 11.83], with a greater increase for tribal adolescents [βtribal-nontribal = 1.53 (95% CI = 0.03, 3.03)]. The intervention also significantly improved internal health locus of control (marginal mean increment 1.38 ± 0.05), self-determination (marginal mean increment 3.71 ± 0.09) and reduced pathological behaviour of the adolescents. ConclusionOur study informed the current health policy that the existing life skills education-based programme should be reviewed and modified to include generic life skills, and the life skills education-based programme should be coupled with developmental interventions aimed at improving adult education and family climate for optimum effect on mental health and health behaviour of adolescents.