Introduction Chronic obstructive pulmonary disease (COPD) represents a major public health challenge in China, with management delivered across all levels of the health system. Medication burden may undermine medication adherence and health-related quality of life (HRQoL), yet the pathways linking these factors remain unclear. This study evaluated the association between medication burden and HRQoL and examined whether medication adherence mediates this relationship from a multilevel health system perspective.Methods A multicentre cross-sectional study was conducted across healthcare institutions participating in the Cough and Wheeze Pharmaceutical Care Clinic network between September 2023 and September 2024. Medication burden was assessed using the total prescribed drugs and the Medication Regimen Complexity Index (MRCI). HRQoL was measured using the EuroQol 5-Dimension 5-Level Questionnaire, and adherence was evaluated with the Adherence to Refills and Medications Scale. Structural equation modelling assessed direct and indirect pathways, and mediation effects were estimated using percentile bootstrapping with 5000 resamples. Sensitivity analyses examined the robustness of the findings.Results A total of 2125 patients with COPD were included. Participants had a median of 1 (IQR 0-2) prescribed medications and a median MRCI of 8.0 (range 0.0-13.5). A higher number of medications was significantly associated with poorer HRQoL both directly (estimate = -0.025, 95% CI -0.038 to -0.012) and indirectly via lower adherence (estimate = -0.007, 95% CI -0.010 to -0.003). While MRCI demonstrated no significant direct association with HRQoL, an indirect effect through adherence was observed (estimate = -0.001, 95% CI -0.002 to -0.001). All findings remained consistent across sensitivity analyses.Conclusions Across multiple levels of the healthcare system, medication adherence partially mediated the association between medication burden and HRQoL in patients with COPD. These findings highlight medication regimen optimisation and adherence support as important public health strategies for improving patient-centred COPD care.