Background: The systemic lupus erythematosus (SLE) patients oftentimes suffer from both physical and psychosocial challenges that may lead to low health-related quality of life (HRQoL). However, limited research has been done in this area. Objective: To examined mental health status and HRQoL among SLE patients in Thailand. Materials and Methods: The present study was a cross-sectional study conducted at the rheumatology clinic of four major hospitals in Thailand. The paper-based questionnaire consisted of demographic, health history such as depression, anxiety, stress Scale (DASS-21), and the Rosenberg self-esteem scale (RSE), and the disease-specific Lupus Quality of Life scale (LupusQoL). Depending on the variable’s level of measurement such as categorical or continuous, Spearman’s Rho or Pearson’s product moment correlation coefficients were used to explore the relationships among the variables. Hierarchical multiple regression was used to identify the predictors of LupusQoL. Results: Among the 387 participants, many might have experienced depression, anxiety, and stress (30%, 51%, and 29%, respectively). Self-esteem among the participants was good (31.8 out of 40). All eight domains of LupusQoL were affected with intimate relationship domain being impacted the most. The overall LupusQoL was significantly associated with the number of prescribed medications (r=–0.23), depression (r=–0.70), anxiety (r=–0.58), stress (r=–0.67), and self-esteem (r=0.59), p<0.001. Significant predictors of the overall LupusQoL were mental health status (depression, anxiety, and stress) and self-esteem, F (3, 81)=43.10, p<0.001, adjusted R²=0.60. Conclusion: SLE patients should be holistically assessed in both physical and psychological aspects. In addition to proper medical treatments, healthcare providers should use a multidisciplinary team approach to resolve the patients’ psychosocial issues, which in turn, may increase the patients’ quality of life. Self-care education may be necessary to help the patients manage the condition and decrease the number of medications. Keywords: Mental health, Quality of life, SLE, Thailand