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Introduction Vaping has risen rapidly among Mexican-American college students in the United States (US), raising concerns about the influences of mental health and digital media. Mexican-Americans are the largest Hispanic subgroup in the US and may face unique sociocultural and environmental risk factors that increase the risk of vaping. While depression and problematic social media use (PSMU), characterized by excessive and compulsive use, are known risk factors, little research has examined their combined impact on vaping behavior. This study examined how PSMU and depressive symptoms independently and interactively influence Mexican-American college students’ susceptibility to vaping. Methods Data were from two waves of the vaping, acculturation, and media study, a prospective longitudinal cohort study. Self-reported online survey data were collected from 828 Mexican-American college students (aged 18–29 years), across six Texas universities, who reported never vaping at baseline (Fall 2023) and completed a 1 year follow-up (Fall 2024). Mixed-effects logistic regression models tested direct effects and an interaction term for PSMU and depressive symptoms on vaping susceptibility, adjusting for sociodemographic factors, anxiety, peer vaping, exposure to pro-vaping content, and cannabis use. Results PSMU significantly predicted greater susceptibility to vaping at follow-up at 1 year (AOR=1.45; 95% CI: 1.18–1.74). A significant negative interaction was observed (AOR=0.81; 95% CI: 0.69–0.97); simple slopes analysis showed that PSMU was associated with greater susceptibility at low (β=0.10, p<0.001) and mean (β=0.07, p<0.001) levels of depressive symptoms, but not at high levels (β=0.04; p=0.102). Conclusions Findings indicate that the association between PSMU and vaping susceptibility varies by level of depressive symptoms among Mexican-American college students. Culturally tailored prevention strategies that integrate mental health screening with interventions targeting PSMU may help reduce curiosity and willingness to initiate vaping.