Drawing on minority stress theory, the present study tested the relations of minority stressors (i.e., experiences of prejudice and discrimination, internalized antitrans attitudes, fear of antitrans stigma), social support (i.e., friend, family, and significant other support), and substance use (i.e., drug and alcohol use) with depression and suicide risk in a sample of trans individuals. Depression was examined as a mediator of the relations of minority stressors and social support with suicide risk; drug and alcohol use were examined as direct correlates of suicide risk. Participants were 335 trans-identified individuals, diverse in gender identities (e.g., trans men, trans women, nonbinary gender identities). They were recruited using online social networks and they completed the study survey online via Qualtrics. Structural equation modeling was used to test hypothesized relations. Depression fully mediated the relations of perceived experiences of discrimination, fear of antitrans stigma, and friend support with suicide risk, and partially mediated the relation of internalized antitrans attitudes with suicide. Drug use was positively associated with suicide risk, whereas alcohol use was not linked with suicide risk. Exploratory comparisons across gender subgroups suggested that the pattern of relations among study variables was consistent across trans men, trans women, and individuals with nonbinary gender identities. These findings point to minority stressors, friend support, and drug use as potentially fruitful targets of prevention and intervention efforts to reduce depression and suicide risk in trans populations.