LGBTQ+ individuals are at increased risk of experiencing mental health concerns including depression and substance use. Understanding these mental health disparities has been an increasing focus for researchers, but there is still limited research on the relationship between religion and depression and substance use among LGBTQ+ individuals. In the current study, it was theorized that higher perceived parental religiosity influences current experiences of depression and alcohol and substance use/abuse through the mediator of the perceived familial stigma of sexuality (stigmatizing behaviors experienced in the home). Individuals (N = 427) who identified as gay/lesbian, queer, bisexual, pansexual, asexual, and/or demisexual were recruited for the study. Results showed that perceived parental religiosity was positively linked to both current reports of depression, alcohol use, and cannabis use. In line with predictions, perceived familial stigma of sexuality was found to fully mediate the relationships between perceived parental religiosity and depression and cannabis use and to partially mediate the relationship between perceived parental religiosity and alcohol use. Furthermore, there was a moderating effect of gender, showing that gay men experienced the strongest links between perceived parental religiosity and perceived familial stigma and between perceived familial stigma and depression, alcohol use, and cannabis use. The findings of this study implicate perceived familial stigma of sexuality as an important factor that could explain how perceived parental religiosity increases LGBTQ+ individuals' experiences of mental health concerns.