Among increased concerns about the adverse health outcomes of inadequate health literacy, it still remains unclear how health literacy influences health-related quality of life (HRQoL) of patients who have undergone percutaneous coronary intervention (PCI). Therefore, the aim of the study was to examine the impact of health literacy on HRQoL in PCI patients at 6 months after discharge. This study used a self-reported questionnaire to assess health literacy, medication knowledge, and HRQoL in 238 patients. In hierarchical linear regression, health literacy was the strongest predictor of HRQoL after adjusting confounding factors (β = .23, p = .003). In addition, this study showed that medication knowledge acted as a partial mediator between health literacy and HRQoL. In conclusion, adequate health literacy is a contributing factor to better HRQoL in patients after PCI, and health literacy can lead to improved HRQoL in PCI patients through the acquisition of sufficient medication knowledge.