Background: Prior research indicates a direct, short-term effect of e-cigarette advertising on e-cigarette use among youth. This study seeks to investigate the long-term effects of e-cigarette advertisements and disparities in exposure among adolescents with different levels of internalizing problems. Methods: Panel data of the Population Assessment of Tobacco and Health (PATH) Study Waves 3–5 (2015–2019) were analyzed. Youth aged 12–17 who were non-e-cigarette users at the time of Wave 3 were included (n = 4,678). A moderated mediation model was employed to examine the mediating role of perceived harm of e-cigarettes and the moderating effect of internalizing problems. Results: Exposure to e-cigarette advertisements in Wave 3 predicted lower harm perception of e-cigarette in Wave 4 (bp = -0.055, p <.01), leading to more e-cigarette use in Wave 5 (bp = -0.042, p <.001). While e-cigarette advertisements exhibited a lasting indirect effect (bp = 0.002, p <.05), there was no long-term direct effect (bp = 0.017, p >.05) on youth e-cigarette use. Furthermore, a moderating effect of internalizing problems was observed (bp = 0.107, p <.05). Conclusions: E-cigarette advertisements can exert a lasting influence indirectly by diminishing harm perception, particularly among those with lower internalizing problems. Adolescents with higher internalizing problems exhibit lower susceptibility to advertisement influence, yet their perceived harm of e-cigarettes is notably lower than their peers with fewer internalizing problems. These disparities underscore the need for tailored prevention strategies: implementing anti-e-cigarette education programs for adolescents with low internalizing problems and providing mental health care for those facing internalizing challenges. Regulatory measures targeting e-cigarette advertising are also crucial.