Purpose Resilience may facilitate the adaptation after experiencing a severe disease such as acute myocardial infarction (AMI) and attenuate the negative effects of stress on health-related quality of life (HRQOL). However, it is unclear so far whether resilience moderates a negative association between work-related stress and HRQOL in employed patients after AMI. Methods Patients with confirmed AMI and regular paid employment admitted to a hospital in the study region of the MONICA/KORA Myocardial Infarction Registry, Germany (04/2014-06/2017) were included and completed questionnaires during their hospital stay and 6 and 12 months after discharge. The Resilience Questionnaire (RS-11) and the Effort-Reward Imbalance (ERI) Questionnaire were used to assess trait resilience and ERI, respectively. HRQOL was measured by the Short Form 36 Health Survey (SF-36) mental and physical component summary scales. Generalized estimating equations (GEE) adjusted for relevant potential confounding variables (demographic, social, stress-related, and clinical) were used to determine the association between resilience and HRQOL in the study course. Results From the 346 patients enrolled in the study, 270 patients (78.0%) had completed all surveys. High baseline trait resilience was significantly and independently associated with high physical HRQOL (ss = 0.15, p < 0.0001) and high mental HRQOL (ss = 0.37, p < 0.0001) 1 year post AMI. No significant interaction effects between trait resilience and ERI were found in the physical HRQOL GEE model (ss = 0.05, p = 0.7241) and in the mental HRQOL model (ss = 0.05, p = 0.3478). Conclusions The results demonstrated that trait resilience is independently and strongly related with post-AMI HRQOL but does not moderate the association between ERI and HRQOL.