BACKGROUND: Renal dysfunction is linked to both the complexity of coronary artery lesions and the prognosis of acute coronary syndrome (ACS). However, the nature of this intricate relationship remains unclear. Therefore, this study aimed to investigate the mechanisms through which coronary lesion complexity mediates the association between renal dysfunction and adverse cardiovascular outcomes in patients with ACS. METHODS: This analysis included 1400 ACS patients who underwent percutaneous coronary intervention (PCI). Renal function was assessed using the estimated glomerular filtration rate (eGFR), calculated according to the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, which incorporates both creatinine and cystatin C. Coronary lesion complexity was evaluated using the baseline SYNTAX score (bSS). The associations among eGFR, bSS, and major adverse cardiovascular events (MACEs) were examined using survival analysis, restricted cubic spline (RCS) analysis, and mediation analysis. RESULTS: A total of 229 MACEs (16.4%) occurred over a median follow-up of 31.03 (27.34, 35.06) months, including 99 all-cause deaths (7.0%), 41 myocardial infarctions (2.9%), and 123 unplanned revascularizations (8.9%). After multivariate adjustment, both the eGFR and bSS significantly predicted MACEs across the total population and various subgroups. Mediation analysis showed that bSS mediated 16.49%, 14.76%, 12.87%, and 11.95% of the correlation between eGFR and MACEs in different adjusted models. CONCLUSION: The relationship between renal dysfunction and MACEs in ACS patients is partially mediated by coronary lesion complexity. This finding underscores the importance of integrating kidney function assessments with coronary anatomical evaluations to develop individualized risk stratification strategies.