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Abstract Background Multimorbidity has a significant impact on public health and primary care. Medication adherence is recognized as the most effective measure for managing and preventing multimorbidity. Studies have shown that medication literacy has a positive effect on medication adherence in patients with multimorbidity. However, limited knowledge exists regarding the underlying mechanisms of this relationship in older adults with multimorbidity. Therefore, the aim of this study was to investigate the mediating role of self-efficacy in the association between medication literacy and medication adherence in this population. Methods This study employed a cross-sectional design and convenience sampling method to survey older patients with multimorbidity in six communities in Zhengzhou, China, from July 12, 2021, to December 15, 2021. Participants were assessed using a demographic questionnaire, the Chinese Version of the Medication Literacy Scale (C-MLS), the Self-Efficacy for Appropriate Medication Use Scale (SEAMS), and the Chinese Version of the Morisky Medication Adherence Scale-8 (C-MMAS-8). Data were analyzed using descriptive statistics, t-tests, one-way analysis of variance, Pearson correlation analysis, and mediation analysis. Results A total of 350 elderly patients met the inclusion criteria, and 328 valid questionnaires were collected. The mean age of the participants was 74.90 ± 7.37 years, with a slightly higher proportion of males (55.8%) than females (44.2%). The mean score for medication adherence was 4.85 ± 1.57, indicating poor medication adherence among the participants. Medication adherence scores varied significantly among participants of different ages, education levels, employment statuses and kinds of medication (p |