This study investigated whether the presence of school-based health centers (SBHCs) was associated with six substance use behaviors among sexual minority youth (SMY) and their heterosexual peers. Data from the 2015 Oregon Healthy Teens Survey, including 13,608 11th graders in 137 schools (26 with SBHCs) were used in the current study. Multilevel logistic regression analyses were performed. Results revealed significant SBHC by SMY status interactions indicating a relatively lower likelihood of past 30-day alcohol use (23%), binge drinking (43%), use of e-cigarettes (22%), marijuana (44%), and unprescribed prescription drugs (28%) among SMY in SBHC schools compared with non-SMY at SBHC schools. Furthermore, SMY in SBHC schools reported lower likelihood of aforementioned substance use behaviors than SMY attending non-SBHC schools. Conversely, no differences in these outcomes were observed for non-SMY in SBHC and non-SBHC schools. Findings from this study suggest SBHCs may help to mitigate substance use disparities among marginalized populations, such as SMY.