Youth homelessness has been demonstrated to disproportionately affect sexual and gender minority (SGM) youth compared to heterosexual cisgender peers. In this context, we aimed to compare health risks between service-seeking SGM and heterosexual cisgender youth experiencing homelessness, including harmful risks stemming from substance use and severity of symptoms of mental health disorders. We recruited 100 racially diverse, unstably housed participants aged 18–24 who access services at an urban non-profit organization in San Francisco, CA. Data analysis included 56 SGM participants who identified as gay, lesbian, bisexual, pansexual, unsure, transgender, and nongender, and 44 heterosexual cisgender participants. In contrast to previous studies reporting significantly higher frequency of substance use and more severe symptoms of depression, generalized anxiety, and posttraumatic stress disorder among SGM youth compared to heterosexual cisgender peers, many of these health disparities were not observed in our diverse study population of service-seeking youth. Furthermore, with the exception of methamphetamine, SGM participants did not exhibit greater harmful risks resulting from substance use, such as health, social, financial, and legal complications. We discuss the reduced burden of health disparities between SGM and heterosexual cisgender youth in our service-seeking study population within the context of gender- and sexuality-affirming programming offered at the partnering community organization. We conclude that longitudinal data on these tailored community-level interventions are needed to further explore the reduced burden of health disparities observed among service-seeking SGM youth experiencing homelessness in San Francisco in order to continue supporting pathways out of homelessness for youth of all sexual and gender identities nationwide.