We aimed to examine the concurrent associations of gender-affirming hormonal interventions (i.e., puberty blockers, testosterone, estrogen), as well as family and friend social support, on transgender and nonbinary (TNB) adolescents' reports of anxiety symptoms, depressive symptoms, nonsuicidal self-injury (NSSI), and suicidality. We hypothesized that gender-affirming hormonal interventions and greater social support would be associated with lower levels of mental health concerns. Participants (n = 75; aged 11–18; Mage = 16.39 years) were recruited for this cross-sectional study from a gender-affirming multidisciplinary clinic. Fifty-two percent were receiving gender-affirming hormonal interventions. Surveys assessed anxiety and depressive symptoms, NSSI and suicidality in the past year, and social support from family, friends, and significant others. Hierarchical linear regression models examined associations between gender-affirming hormonal interventions and social support (i.e., family, friend) with mental health while accounting for nonbinary gender identity. Regression models explained 15%–23% of variance in TNB adolescents' mental health outcomes. Gender-affirming hormonal interventions were associated with fewer anxiety symptoms (β = −0.23; p < .05). Family support was associated with fewer depressive symptoms (β = −0.33; p = .003) and less NSSI (β = −0.27; p = .02). Friend support was associated with fewer anxiety symptoms (β = −0.32; p = .007) and less suicidality (β = −0.25; p = .03). TNB adolescents had better mental health outcomes in the context of receiving gender-affirming hormonal interventions and having greater support from family and friends. Findings highlight the important role of quality family and friend support for TNB mental health. Providers should aim to address both medical and social factors to optimize TNB mental health outcomes.