Background: Although schools often implement evidence-based sexual health education programs to address sexual and reproductive health disparities, multiple factors may influence program effectiveness. Methods: Using student-reported perceived impact measures as a proxy for program effectiveness, we employed a socio-ecological approach to examine student, teacher, school, and district factors associated with greater perceived impact of It's Your Game (IYG), an evidence-based middle school sexual health education program. The student sample was 58.7% female, 51.8% Hispanic, mean age 13.2 years, from 73 middle schools. We assessed students' (N = 4531) perceived impact of IYG on healthy decision-making ([alpha] = 0.75) and sexual communication ([alpha] = 0.71); satisfaction with IYG activities and teacher; and demographics. We assessed teachers' (N = 56) self-efficacy to teach IYG, perceived administrative support, implementation barriers, and demographics. School and district data were abstracted from state records. We used multilevel logistic regression to estimate associations between independent variables and student-reported perceived impact. Results: In final multivariate models, students' demographics (sex, [beta] = 0.06, SE = 0.015), satisfaction with IYG ([beta] = 0.21, SE = 0.012), and their IYG teacher ([beta] = 0.18, SE = 0.013) (all p = 0.000) were significantly associated with perceived impact on healthy decision-making. Similar findings resulted for sexual communication. No other variables were significantly associated with perceived impact. Conclusions: Helping schools select age-appropriate, culturally relevant programs, and facilitate supportive learning environments may enhance the perceived impact of sexual health education programs.