Background: Electronic cigarette (e-cigarette) use among adolescents is a growing public health concern, particularly in low-income and Black communities. However, little is known about how social determinants of health shape e-cigarette perceptions in this population. Aims: This study examined social determinants associated with perceptions of e-cigarette safety among Baltimore high school students. Methods: A cross-sectional survey (CEASE Youth: School Survey) was conducted with 604 Baltimore high school students aged 14–20. Participants completed a questionnaire assessing perceptions of e-cigarette safety, as well as parental education, race/ethnicity, parental employment, household composition, and community tobacco use. Results: Higher parental education was associated with lower perceived e-cigarette safety among students. Students in higher grades also reported lower perceived e-cigarette safety. In contrast, male students—particularly those in upper grades—were more likely to perceive e-cigarettes as safe. Race/ethnicity, household composition, parental employment, and community tobacco exposure were not associated with perceived e-cigarette safety. Conclusion: Higher parental education, female gender, and being in higher grades were associated with perceiving e-cigarettes as unsafe. These findings highlight the need for targeted interventions to address vaping perceptions among youth in urban settings.