Sexual minorities were surveyed about their experiences during the pandemic, and asked about symptoms of PTSD, minority stress, anxiety/depression, and substance use. We surveyed 392 sexual minorities who self-identified as substance users, including 70 of whom also identified as a gender minority. Participants completed questionnaires that included demographic questions, COVID-related PTSD symptoms [Post Traumatic Stress Checklist for the DSM-5 (PCL-5)], minority stress [Minority Stress Scale (MSS)], anxiety/depression [Patient Health Questionnaire - 4 (PHQ-4)], and substance use [adaption from the Alcohol Use Disorders Identification Test (AUDIT)]. A serial mediation model was used and we found an indirect relationship between minority stress and substance use through anxiety/depression and COVID-related PTSD such that minority stress positively predicted anxiety/depression, which in turn predicted COVID-related PTSD; and then predicted substance use in sexual minorities. Sexual minorities experienced greater health disparities during the COVID-19 pandemic. Sexual minorities high in minority stress experienced increased rates of psychiatric symptoms, making them more vulnerable to substance use. These results underscore the need for medical and mental health professionals to address the role of minority stress, and possible substance use and abuse as a method of dealing with psychiatric symptoms and stressors.