Background: Cardiovascular disease (CVD), a chronic and debilitating physical condition, is one of the most common causes of death. Complications of CVD, such as decreased physical and mental health along with its chronic, progressive, and irreversible nature have numerous negative consequences for patients. This study aimed to investigate the mediating role of perceived stress in the relationship between psychological hardiness and quality of life (QoL) in cardiovascular patients. Methods: The present study was a descriptive-correlational and structural equation modeling. The statistical population included all patients with CVD referred to heart hospitals and cardiac rehabilitation centers in Tehran, Iran in 2019. Using purposeful sampling method, a total of 151 individuals were selected. Data collection tools included a Kobasa Psychological Hardiness Questionnaire, Cohen’s Perceived Stress Questionnaire, and Quality of Life Scale (SF-36). To analyze the data, Pearson’s correlation coefficient and path analysis with SPSS.22 and Amos.22 software were used. Results: The results showed that negative perception of stress and positive perception of stress had a significant negative and positive relationship with dimensions of QoL, respectively (P<0.001). Psychological hardiness had a significant positive relationship with dimensions of QoL (P<0.001). Also, perceived stress had a mediating role in the relationship between psychological hardiness and QoL dimensions (P<0.001). Conclusion: The results of the present study indicated a correlation between psychological hardiness and increased QoL and the inverse relationship between perceived stress and QoL in cardiovascular patients.