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Aim: The aims of the study were to analyse the current situation of health literacy (HL), self‐management and health‐related quality of life (HRQOL) in patients with diabetic peripheral neuropathy (DPN), to explore the correlation between the three and to verify the mediating role of self‐management in HL and HRQOL. Design: A cross‐sectional survey. Methods: The convenience sampling method was used to select 401 DPN patients attending the First Hospital of Jinzhou Medical University in Liaoning Province, China, from December 2020 to December 2021 as the study population. The research instrument included socio‐demographic characteristics questionnaire, Health Literacy Management Scale (HeLMS), Summary of Diabetes Self‐Care Activities (SDSCA) and Short‐Form 12‐item Health Survey (SF‐12). SPSS 25.0 was applied to the data for descriptive analysis, Pearson correlation analysis and stratified multiple regression analysis. Mediating effects were tested using SPSS PROCESS macro 4.0 software. Results: HL and self‐management of DPN patients correlated positively with HRQOL. The mediation role of self‐management was significant in the relationship between HL and physical and mental HRQOL (physical component summary: β = 0.26, P < 0.01; mental component summary: β = 0.18, P < 0.01), with mediating effects accounting for 35.62% and 34.62% of the total effect. Conclusions: There was a positive correlation between HL, self‐management and HRQOL in patients with DPN. Self‐management plays a partially mediating role in the relationship between HL and HRQOL in DPN patients. It means that HRQOL in this population can be improved by increasing HL and thus self‐management in DPN patients. Patient or Public Contribution: None. [ABSTRACT FROM AUTHOR]