Patients with acute coronary syndrome (ACS) often experience reduced health-related quality of life (HRQOL), which may be attributable to the disease severity and psychological stress. While illness perception is speculated to be a potential pathway underlying these relationships, evidence supporting this mechanism remains limited. This study aimed to investigate the relationships between disease severity, psychological stress, and HRQOL and whether these relationships are mediated by illness perception in patients with ACS. Data were collected from June to July 2019 and June to September 2020 in the cardiology departments of four public hospitals in China. Eligible patients completed measures of disease severity, psychological stress, illness perception, HRQOL, and sociodemographic and clinical characteristics. Data were analyzed employing hierarchical multiple regression and structural equation modeling. This study included 405 participants (mean age 60.63 years, 67.4% male). After controlling for sociodemographic and clinical covariates, higher levels of disease severity (β=0.115, P=0.024) and psychological stress (β=-0.209, P<0.001) were associated with poorer HRQOL; however, the relationships became non-significant after adding illness perception into the regression model. Structural equation modeling analysis suggested that illness perception played a mediating role between disease severity, psychological stress, and HRQOL, accounting for 45.95% and 65.79% of the total effects, respectively. This study found that illness perception mediated the relationships between disease severity, psychological stress, and HRQOL among patients with ACS. Improving patients' HRQOL should consider its important influencing factors with a focus on promoting positive illness perception.