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Research at the intersection of substance use and protective factors among transgender youth is scarce; emerging evidence suggests high risk for substance use for transgender youth. We analyzed data from 323 transgender youth aged 14–18 (M_age = 16.67) to investigate the extent that risk (enacted stigma) and protective factors (support from family, school, friends) were related to substance use (i.e., cannabis and tobacco use, binge drinking). Enacted stigma was linked to higher odds of substance use behaviors, family connectedness was related to lower levels of tobacco and cannabis use, and more than one protective factor significantly lowered the probability of engaging in substance use behaviors. Support from multiple sources may be differentially protective against substance use for transgender youth.