Parkinson's disease (PD) is characterized by the aggregation and prion-like propagation of α-synuclein (α-syn). Irisin is an exercise-induced myokine that regulates energy metabolism and exerts protective effects in PD by reducing α-syn pathology. However, the molecular mechanisms underlying the role of irisin are not fully understood. Here, we show that irisin inhibits NLRP3 inflammasome activation and promotes autophagy in cultured cells. Additionally, irisin alleviates oxidative stress and reduces cell apoptosis induced by α-syn fibrils. In a PD mouse model induced by intrastriatal injection of α-syn fibrils, irisin mitigated α-syn aggregation, neuroinflammation and neurodegeneration. These observations suggest that irisin functions as a protective mediator against α-syn pathology in PD and that irisin may serve as a potential therapeutic target for the prevention and treatment of PD.