Background: Return to work following myocardial infarction (MI) represents an important indicator of recovery. However, MI can cause patients to feel pressure, loneliness and inferiority during work and even detachment from employment after returning to work, which may affect their quality of life. The aims of this study were to identify the influencing factors of Health-related quality of life (HRQoL) in patients with MI after returning to work and explore the correlations between these factors and HRQoL. Method: This was a cross-sectional study. All participants were recruited from tertiary hospitals in China from October 2017 to March 2018. The general data questionnaire, Short-Form Health Survey-8 (SF-8), Health Promoting Lifestyle ProfileII (HPLPII), Medical Coping Modes Questionnaire (MCMQ) and Social Supporting Rating Scale (SSRS) were used to assess 326 patients with myocardial infarction returned to work after discharge. Multiple linear regression analysis was performed to explore factors related to HRQoL in patients with MI after returning to work. Results: The sample consisted of 326 patients. The mean total score of quality of life was 28.03 ± 2.554. According to the multiple linear regression analysis, next factors were associated with better HRQoL: younger age (B = − 0.354, P = 0.039), higher income (B = 0.513, P = 0.000), less co-morbidity (B = − 0.440, P = 0.000), the longer time taken to return to work (B = 0.235, P = 0.003), fewer stents installed (B = − 0.359, P = 0.003), participation in cardiac rehabilitation (CR) (B = − 1.777, P = 0.000), complete CR (B = − 1.409, P = 0.000), better health behaviors such as more health responsibility (B = 0.