Latinos are a multiracial ethnic group, and as such, within-group differences in ethnoracial appearance deserve to be studied and understood within the racialized American context and in connection to specific health and mental health outcomes. This article presents the findings of a study conducted with middle school Mexican heritage students (n = 1,150) in Phoenix, Arizona, and tested how non-White majority ethnoracial appearance predicted adolescent substance use, and whether the relationship differed by generation status and strength of ethnic identity. Logistic regression results revealed that generation status and ethnic identity moderate the relationship between ethnoracial appearance and substance use among Mexican heritage youth. The odds of using substances were significantly higher for third-generation adolescents who reported a less European appearance, but significantly lower for second-generation youth who were more indigenous in appearance. These findings indicate that a stronger indigenous ethnic appearance can be both a protective and risk factor for substance use for adolescents. Implications are discussed in terms of incorporating ethnoracial appearance content in prevention interventions for Mexican heritage and other Latino adolescents. (Contains 2 tables and 1 figure.)