Differentiated thyroid carcinoma (DTC) patients are associated with excellent prognosis but impaired health-related quality of life (HRQOL) by initial and subsequent therapy. Health literacy plays a pivotal role in public health and medical settings, but data on its relationship with DTC patients' HRQOL are insufficient and equivocal. This study was designed to explore the relationship between health literacy and HRQOL in patients with DTC from West China areas.A cross-sectional study with a descriptive correlational design was conducted. 126 patients with DTC were recruited between 2020 and 2021. Levels of health literacy and HRQOL (including fatigue level, anxiety/depression status, and somatoform symptoms) were assessed by questionnaires. Pearson product-moment correlation and Stepwise multiple regression were used to examined the adjusted association of health literacy with HRQOL.Health literacy and receiving DTC-related education together explained 16.2% of the variance in fatigue level. Patients who had higher health literacy, received more DTC-related education were currently employed and less fatigue. Health literacy, fatigue level and DTC-related education together explained 31.0% of the variance in anxiety and depression of DTC patients. Patients who had higher health literacy, received more DTC-related education and less fatigue level were less anxious and depressive. Age explained 8.3% of the variance in DTC patients' somatoform symptoms. Older patients complained more somatoform symptoms.Health literacy was positively associated with HRQOL in DTC patients regarding to fatigue level and anxiety/depression status across the entire sample. Interventions to improve HRQOL should take the patients' health literacy into account.© 2023 The Authors. Health Science Reports published by Wiley Periodicals LLC.