Purpose <p>While transgender and non-binary (TNB) people face stress and oppressions placing them at greater risk of depression and anxiety compared to cisgender people, little research has explored mental health differences between subgroups. Drawing on an intersectionality framework, which examines how oppressive forces interact to impact health, this study investigated intersecting factors associated with mental health outcomes among TNB people in Canada.</p> Methods <p>Data were from Trans PULSE Canada’s 2019 community-based, national survey of health and wellbeing among TNB people. Respondents reported sociodemographic characteristics, sex work history, disability, neurodiversity, sense of belonging in TNB spaces, and mental health. We conducted three conditional inference tree analyses to determine the combinations of social factors that predict depression, anxiety, and thriving.</p> Results <p>Analyses included 2058 respondents (Mean age = 31.1, <i>SD</i> = 11.1). Reporting age 16–49 years, physical/visible disability, sex work history, and/or lower socioeconomic status generally predicted poorer mental health. Among respondents below the low-income threshold, a sense of belonging in TNB spaces was associated with more thriving, but only if they were not autistic. For individuals with physical/visible disability, a sense of belonging predicted greater thriving and less depression.</p> Conclusion <p>Results highlight intersecting social and structural factors associated with increased risk of poor mental health among specific groups of TNB people, including lower socioeconomic status and/or a physical/visible disability, or being &lt; 50 with a history of sex work. Individuals with better mental health reported more belonging in TNB spaces, which may suggest that sense of belonging in TNB spaces is protective.</p> Trial registration <p>Not applicable.</p>