Hyperuricemia is associated with kidney function decline (KFD), although whether hyperuricemia directly causes nephrotoxicity or is indirectly mediated by systemic arterial stiffening remains unclear. We examined the detailed relationship of serum uric acid (SUA) with KFD and potential mediation by arterial stiffness. Study population was 27,648 urban residents with an estimated glomerular filtration rate (eGFR) of ≥60 mL/min/1.73 m at baseline, and they participated in a median of three consecutive annual health examinations. Arterial stiffness was assessed using cardio-ankle vascular index (CAVI). KFD was defined as a decrease in eGFR to below 60. Multivariate analysis showed an association between baseline SUA and CAVI independent of eGFR. During the study period, 6.6% of participants developed KFD. Stratified analysis revealed a linear relationship between the contribution of CAVI or SUA and KFD. ROC analysis determined a cutoff CAVI of 8.0 (males) or 7.9 (females) and a cutoff SUA of 6.3 (males) or 4.5 mg/dL (females) for predicting KFD. The linkage between SUA and CAVI was associated with a greater increase in the hazard ratio for KFD with an increase in SUA. CAVI showed the mediating effect on the relationship of SUA with KFD after an adjustment for confounders. SUA was associated positively with CAVI-mediated KFD. Further studies should verify whether intensive SUA-lowering treatment prevents KFD via improving vascular function.