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Background: Transgender women of Color experience disproportionate rates of HIV, depression, and anxiety, and high rates of substance use, attempted suicide, and interpersonal verbal, physical, and sexual violence and assault. However, there are few interventions targeting transgender women of Color that address overlapping health and mental health challenges. Aims: There are two aims/research questions: (1) what are the elements of a transgender-centric model for delivering evidence based interventions and practices?, and (2) does Seeking Safety improve substance use and mental health outcomes for transgender women of Color? Methods: We present a case study of the delivery process of Seeking Safety by Special Service for Groups/Asian Pacific AIDS Intervention Team (SSG/APAIT), and analyze baseline and three month post program participant data (n = 81). Results: The transgender-centric model of intervention delivery consisted of multiple steps, also integrating the structural disadvantages experienced by transgender women of Color. Comparing baseline and three months after completion showed significant decrease in reported alcohol use, depression, and severe anxiety. Discussion: Transgender-centric approaches may lead to programs that significantly improve co-occurring substance use and mental health for transgender women of Color. We recommend that organizations aiming to existing programs include feedback from members of the communities that the adapted programs aim to help, and in addition, train community members to deliver the programs. The statistical results indicate that Seeking Safety, a trauma-based program with a short program delivery timeline, may show longer term effects on substance use and mental health. We recommend that programs targeting substance use and mental health for transgender women of Color should be combined with services that address disadvantage (i.e., lack of access to housing, income/employment, health care).