INTRODUCTION: The E-cigarette industry's marketing and social media efforts have promoted adolescent vaping. We developed and pilot-tested an anti-vaping media literary program-MediaSense. AIMS AND METHODS: In addition to employing the Community-Based Participatory Research approach for program development, we applied a prospective, interventional, and single-arm design to assess the impact of MediaSense among students from five middle and high schools. Data were collected through REDCap surveys administered before and after the intervention. We performed generalized linear mixed models and median analysis to evaluate changes in vaping media literacy (ie, Authors and Audiences [vAA], Messages and Meanings [vMM], and Representation and Reality [vRR]), knowledge, harm perception, and susceptibility to e-cigarette use before and after the intervention. RESULTS: A total of 384 students aged 11-18 years completed the pre-post survey assessment. After the intervention, students exhibited significantly improved vaping media literacy across all three domains (vAA, fold change [FC] = 150%, p <
.0001
vMM, FC = 143%, p <
.0001
vRR, FC = 133%, p = .0007). The intervention was associated with a reduction of vaping susceptibility (adjusted odds ratio [AOR] = 0.7, p = .04) and improvement in harm perception (AOR = 1.6, p = .009), knowledge of flavored e-cigarettes (AOR = 4.4, p <
.0001) and Tobacco 21 policy (AOR = 6.2, p <
.0001). Further mediation analysis unveiled the pathway of the intervention on reduction of vaping susceptibility through media literacy (βindirect = -0.03, p = .003) and harm perception enhancement (βindirect = -0.02, p = .03). CONCLUSIONS: The MediaSense program showed promise in vaping prevention among adolescents by reducing vaping susceptibility. Comprehensive vaping media literacy education, especially interventions aimed at decoding misleading marketing information and addressing emerging marketing themes, provides valuable evidence in curbing adolescent vaping. IMPLICATIONS: MediaSense (Media Education for Sensible Evaluation and Nurturing Substance-free Experiences) represents a promising e-cigarette education program designed for adolescent vaping prevention. The findings of this study highlight the positive impact of the program on media literacy, harm perception, and knowledge of tobacco control policies.