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Background: In Vietnam, there is a paucity of health-related quality of life (HRQoL) research on people with depression as well as a lack of evidence on supported self-management (SSM) intervention for depression on HRQoL. This study aimed to compare the HRQoL of people with depression and age-matched people in the Vietnamese population, evaluate the effects of Tele-SSM intervention on HRQoL, and examine the association between the changes in HRQoL score and mental health well-being (depression, anxiety, and stress). Methods: This study was a pre- and post-study involving Vietnamese adults aged 18–64 who had depression symptoms (score ≥ 5 points in the PHQ-9). Participants (N = 58) completed Tele-SSM—a supported self-management intervention incorporating cognitive behavioral therapy and non-violent communication and using a task-shifting approach. To compare with the general population, we conducted a 1-to-1 matching by age with an EQ-5D-5L valuation study with a nationally representative sample of the Vietnamese general population. Results: HRQoL was significantly impaired in people with depression compared to the age-matched general population. Regarding health profile, participants reported the most difficulties in usual activities, pain/discomfort, and anxiety/depression dimensions. Significant improvements were observed in HRQoL scores post-intervention compared to pre-intervention in both EQ-VAS scores (from 59.84 to 79.48) and utility scores (from 0.79 to 0.90). These results remained lower than the age-matched general population (EQ-VAS score = 83.28, utility score = 0.96). Depression was associated with lower HRQoL while controlling for stress, anxiety symptoms and sociodemographic characteristics. Conclusions: These results indicate that HRQoL is significantly impaired in people with depression and contribute to providing empirical evidence of Tele-SSM intervention in improving HRQoL. Further randomized controlled trials should be conducted to evaluate the effectiveness and cost-effectiveness of the Tele-SSM intervention. [ABSTRACT FROM AUTHOR]