Research suggests that transgender and non-binary (TGNB) individuals experience lower levels of psychological well-being than the general population. Although practice recommendations and guidelines exist, there is a paucity of studies evaluating the effects of psychological interventions on this group. This systematic review aimed to synthesize and analyze existing empirical affirmative psychological interventions for TGNB individuals to assess their efficacy. Eight databases (PubMed, Web of Science, PsycINFO, Scopus, LILACS, Cochrane, ProQuest, Google Scholar) were searched from January 2010 to June 2022 to identify relevant studies. Included studies needed to be randomized controlled trials, quasi-experimental, or uncontrolled pre-post. Twenty-two articles were included, of which eight had TGNB participants only, two had mixed samples with separated outcome data for TGNB participants, and 12 had mixed samples with no disaggregated data. Experimental designs, participant samples, assessed variables, and type of interventions varied widely across studies, thus preventing comparisons. Overall results suggest improvements in psychological distress, depression, anxiety, suicidality, substance-related risk behaviors, coping skills/emotion regulation, stress appraisal, self-esteem, self-acceptance, social support, minority stress, resilience, hope, positive identity, and identity acceptance, although conclusions are limited by moderate-to-high risk of bias. Future research should implement more consistent and rigorous methodological designs to assess and compare intervention efficacy. •Transgender and non-binary individuals show low levels of psychological well-being.•Studies gauging the effects of psychological treatments for this group are scarce.•Results suggest improvements in mental health and gender minority stress variables.•The quality of evidence was moderate-to-low, so more rigorous research is needed.