BACKGROUND School‐based health centers (SBHCs) have been associated with many positive health and academic outcomes. The current study extends previous research and examines possible differences in the association between SBHC exposure and adolescent alcohol, tobacco, and other drug use by race/ethnicity, sex, and socioeconomic status (SES). METHODS California Healthy Kids Survey data from 504 traditional high schools in California were linked with publicly available data on SBHCs and school demographics. Multilevel logistic regression analyses were conducted controlling for school and individual characteristics. RESULTS Significant interactions suggest that SBHC exposure was inversely associated with past 30‐day alcohol use, binge drinking, and cigarette and e‐cigarette use among African American youth and negatively associated with cigarette and marijuana use among Asian youth, relative to whites. There was also a significant interaction between SBHC exposure and parent education for past 30‐day alcohol use and binge drinking. No significant sex interactions were observed. CONCLUSIONS SBHC exposure appears to be inversely related to substance use among youth in some ethnic minority groups and youth of lower SES. This may have implications regarding SBHC placement and investment. Additional research is necessary to understand the mechanisms through which SBHCs may influence adolescent substance use and other health behaviors.