This paper examines the extent to which transgender students' experiences with school-based victimization and school protective factors contribute to or reduce substance use. We conducted secondary analyses of school-based victimization, school protective factors, and substance use of a subsample of transgender students from the 2013-2015 California Healthy Kids Survey. Results indicate that among transgender students, school-based victimization is a risk factor for substance use. School protective factors, including school connectedness and school adult support, were associated with a decreased likelihood of substance use among transgender students; for instance, higher levels of school connection were associated with a 30% decreased odds of past 30-day cigarette use (AOR = 0.70; 95% CI = 0.60-0.82), above and beyond the key risk factor of school-based victimization. This study's findings suggest that school educators, staff, and administration should receive training around transgender-inclusive practices, and schools should implement transgender-affirming education, programming, and services to improve school connection and school adult support for transgender students.