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Loneliness is a significant risk factor for depression in adults. Sexual and gender minority (SGM) individuals are at risk for loneliness and depression due to stigma and discrimination. However, little is known about the influences of loneliness on the mental health of SGM populations. Guided by the Minority Stress and Integrative Mediation Frameworks, the authors aimed to examine loneliness's direct and indirect effects on the relationships between minority stressors and depression among Thai SGM adults. Data were drawn from a larger cross-sectional survey. Standardized measures of minority stressors (discrimination, victimization, identity concealment, and internalized sexual stigma), loneliness, and depression were selected and translated by expert panels. A convenience sample was recruited, and data were collected using online and in-person methods. Participants (N = 411, M = 29.5 years) were primarily male (90.5%), gay (79.3%), and cisgender (76.6%). More than 40% of participants reported clinically significant levels of loneliness (M = 38.59, standard deviation [SD] = 11.11) and depression (M = 9.46, SD = 8.43). Discrimination, identity concealment, and internalized sexual stigma were directly associated with loneliness (all p < 0.05). Minority stressors were significantly related to depression through indirect associations via loneliness accounting for 33%-54% of the total effect. Indirect effects (95% confidence interval) were 0.25 [0.12, 0.40] for discrimination, -0.41 [-0.67, -0.18] for identity concealment, and 0.42 [0.06, 0.79] for internalized sexual stigma. Loneliness was prevalent and played a mediating role in the associations between minority stressors and depression. Study findings have implications for the development of intervention research., (© 2022 Wiley Periodicals LLC.)