Introduction Previous studies have reported low quality of life scores and a high prevalence of depression among transgender women in Thailand; however, there is still little research on the effects of gender confirmation surgery among this population. Aim This study aims to prospectively evaluate the overall quality of life, self-esteem, and depression status among male-to-female transgender individuals in Thailand. Methods This prospective observational cohort study was conducted between January 2018 and December 2020 and included 41 participants who underwent gender confirmation surgery. All participants underwent a psychiatric evaluation and received 3 sets of questionnaires preoperatively and 6 months postoperatively to evaluate quality of life, self-esteem, and depression: the Thai abbreviated version of the World Health Organization quality of life questionnaire, the Rosenberg Self-Esteem Scale, and the Patient Health Questionnaire-9, respectively. We examined scores from each questionnaire and depression status before and after gender confirmation surgery, with P < .05 considered significant. Main Outcome Measure This study's primary outcomes measured quality of life, depression, and self-esteem before and after gender confirmation surgery. Results Thirty-seven participants completed all sets of questionnaires (response rate 90.2%). The mean age of the participants was 26.2 ± 4.7 years at the time of surgery. Five (13.5%) participants met the criteria for mild depression preoperatively, but none did postoperatively. There were no signs of major depressive disorder, suicidal ideation, or suicidal attempts in any of the participants. There was a significant improvement in quality of life (P < .001) and self-esteem (P < .001), as well as lower depression (P < .001) after gender confirmation surgery. The greatest quality of life improvement was related to participants’ sexual relationships. Conclusion Male-to-female gender confirmation surgery significantly contributes to improving quality of life, self-esteem, and depression in Thai transgender women. Persons diagnosed with gender dysphoria who intend to undergo gender confirmation surgery should be supported by healthcare providers in accessing the medical facilities and treatment needed to improve their quality of life.