Parkinson's disease-associated cognitive impairment (PD-CI) is closely linked to α-synuclein (α-syn) accumulation and synaptic dysfunction, yet effective disease-modifying strategies remain limited. Irisin is an exercise-inducible myokine with neuroprotective potential, but its receptor mechanisms and its role in α-syn clearance in PD-CI are poorly defined. Here, we observed that aerobic exercise markedly increased circulating irisin levels, reduced serum α-syn levels, and improved cognitive performance in a cohort of 21 PD patients. In addition, irisin signals through integrin αV/β5 to enhance microglial α-syn clearance, resulting in reduced α-syn burden and improved PD-CI. Mechanistically, irisin activates integrin αV/β5-FAK axis to promotes microglial phagocytic uptake of α-syn, while concurrently stabilizing HMGB1 to facilitate autophagy-lysosome mediated degradation of internalized α-syn, thereby coupling phagocytic uptake to efficient degradation. In summary, these results highlight a dual-module irisin-integrin αV/β5 mechanism that couples microglial phagocytosis and autophagy-lysosome clearance to reduce α-syn burden and ameliorate PD-CI.