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LGBTQ+ youth are at elevated risk for suicidality, substance use, and other mental health concerns. Evidence-based psychotherapeutic interventions are often the first line treatment for mental health concerns. However, there is limited research examining the effectiveness of such interventions among LGBTQ+ adolescents. This systematic review synthesizes extant literature examining psychotherapeutic interventions for LGBTQ+ adolescents with mental illness and/or substance use. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, studies were assessed for inclusion eligibility. Researchers consulted three electronic databases, yielding a total of 666 results. Ten studies, with interventions ranging from drug use prevention to school-counseling, met inclusion criteria. Seven studies implemented adaptations to standard intervention protocol to make intervention content more accessible to LGBTQ+ clients. Outcomes included decreased depressive symptoms, substance use, and social isolation. Significant design and methodological limitations were present across most studies, with four using a case study design and only two using a randomized controlled trial design. The review highlights preliminary evidence supporting the use of mental health interventions for LGBTQ+ youth. However, more rigorous research is needed to determine if adapted interventions that include population-specific concerns of minority stress are more effective than treatment as usual.