OBJECTIVE: We examined the direct and indirect impact of minority stress on mental health and substance use among sexual minority women. METHOD: A combination of snowball and targeted sampling strategies was used to recruit lesbian and bisexual women (N = 1,381) for a cross-sectional, online survey. Participants (M age = 33.54 years; 74% White) completed a questionnaire assessing gender expression, minority stressors (i.e., victimization, internalized homophobia, and concealment), social-psychological resources (i.e., social support, spirituality), and health-related outcomes. We used structural equation modeling to test associations among these factors, with gender expression as an antecedent and social-psychological resources as a mediator between minority stress and health. RESULTS: The final model demonstrated acceptable fit, χ²(79) = 414.00, p < .05, confirmatory fit index = .93, Tucker-Lewis index = .91, standardized root-mean-square residual = .05, root-mean-square error of approximation = .06, accounting for significant portions of the variance in mental health problems (56%) and substance use (14%), as well as the mediator social-psychological resources (24%). Beyond indirect effects of minority stress on health outcomes, direct links emerged between victimization and substance use and between internalized homophobia and substance use. CONCLUSIONS: Findings indicate a significant impact of minority stressors and social-psychological resources on mental health and substance use among sexual minority women. The results improve understanding of the distinct role of various minority stressors and their mechanisms on health outcomes. Health care professionals should assess for minority stress and coping resources and refer for evidence-based psychosocial treatments.