The aim of this study is to evaluate and determine The prevalence of depression and suicidality is high among men who have sex with men (MSM) and transgender women (TGW) worldwide. Stigma and discrimination are likely contributing factors. More research is needed in low-income, non-English speaking countries to assess the effects of social and structural factors on depression and suicidality among MSM and TGW. Nepalese MSM and TGW (n = 340) were recruited using a respondent-driven sampling design and filled out a survey questionnaire. The outcomes were depression and suicidality. Data was analyzed using bivariate and multivariable logistic regression. More than half of the participants (59%) suffered from depression. Severe depression was more common among TGW compared to MSM (41 and 20%, respectively). When it comes to suicidality, TGW had higher lifetime prevalence of suicidal thoughts compared to MSM. Nepalese MSM and TGW suffer from a high degree of mental and psychosocial health issues. Future studies should focus on intervention research and on collecting data from a larger variety of gender and sexual minorities.