Polysubstance use is associated with myriad short- and long-term health outcomes. Although prior research has documented differences in polysubstance use between lesbian, gay, bisexual, transgender, queer/questioning, and other sexual and gender minoritized (LGBTQ +) youth and their heterosexual/cisgender counterparts, as well as between subgroups of LGBTQ + youth, it is unknown how personal, family, and school factors are associated with substance use patterns among LGBTQ + youth. Using a large, national sample of 9646 LGBTQ + youth ages 13-17, we used latent class analysis to examine patterns of alcohol, tobacco, and marijuana use and to determine whether personal, family, and school factors predict class membership. We identified five classes of substance use: polysubstance use, polysubstance experimentation, dual alcohol and cannabis, alcohol, and no use. Greater depression and LGBTQ + victimization, and an ability to be oneself at school, were associated with greater odds of membership in the polysubstance use class, while higher levels of family connection and having a Gender Sexuality Alliance (GSA) at school were associated with lower odds of membership in the polysubstance use class. Our analysis also revealed sociodemographic differences in class membership. These findings highlight potential mechanisms for intervention to reduce polysubstance use among LGBTQ + youth.