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Objectives: The objective of this study was to characterize mental health issues among Vietnamese healthcare workers (HCWs) and to identify related factors., Methods: A cross-sectional study was conducted with 990 HCWs in 2021. Their mental health status was measured using the Depression, Anxiety, and Stress Scale., Results: In total, 49.9%, 52.3%, and 29.8% of respondents were found to have depression, anxiety, and stress, respectively. The multivariable linear regression model revealed that factors associated with increased anxiety scores included depression scores (β, 0.45; 95% confidence interval [CI], 0.39 to 0.51) and stress scores (β, 0.46; 95% CI, 0.41 to 0.52). Factors associated with increased depression scores included being frontline HCWs (β, 0.57; 95% CI, 0.10 to 1.10), stress scores (β, 0.50; 95% CI, 0.45 to 0.56), and anxiety scores (β, 0.41; 95% CI, 0.36 to 0.47), while working experience was associated with reduced depression scores (β, -0.08; 95% CI, -0.16 to -0.01). Factors associated with increased stress scores included working experience (β, 0.08; 95% CI, 0.00 to 0.16), personal protective equipment interference with daily activities (β, 0.55; 95% CI, 0.07 to 1.00), depression scores (β, 0.54; 95% CI, 0.48 to 0.59), and anxiety scores (β, 0.45; 95% CI, 0.39 to 0.50), while age was associated with reduced stress scores (β, -0.12; 95% CI, -0.20 to -0.05)., Conclusions: Specific interventions are necessary to enhance and promote the mental health of HCWs so they can successfully cope with the circumstances of the pandemic.