Objective <p>This study aims to assess the level of medication adherence among patients with atrial fibrillation through a longitudinal follow-up study design. Additionally, it seeks to examine the impact of baseline medication literacy on long-term medication adherence and to investigate the mediating role of self-efficacy for appropriate medication use over time. </p> Methods <p>A convenience sampling method was employed to select 579 patients with atrial fibrillation from a tertiary first-class hospital in Hefei, Anhui Province, between May 2023 and June 2024. Data collection occurred at three time points: baseline (T1), where general demographic data and a medication literacy questionnaire were administered; at 3 months (T2), where self-efficacy for appropriate medication use was assessed; and at 6 months (T3), where medication adherence was evaluated. The primary endpoints were measured using the medication adherence score, and the longitudinal relationships were evaluated through mediation analysis.</p> Results <p> At time point T3, the medication adherence score for patients with atrial fibrillation was 34.53 ± 14.19 (total score: 60). Mediation analysis revealed that medication literacy at T1 positively predicts self-efficacy for appropriate medication use at T2, which in turn positively predicts medication adherence at T3. Notably, 13.38% of the total effect of T1 medication literacy on T3 medication adherence is mediated through T2 self-efficacy, functioning as a longitudinal intermediary variable.</p> Conclusion <p>There is a need for improvement in the long-term medication adherence of patients with atrial fibrillation. Early enhancement of medication literacy not only is associated with patients' adherence to medication regimens but also may indirectly be associated with long-term adherence by improving their self-efficacy mid-study.</p>