Recent studies have reported that platelet factor 4 (PF4), also known as platelet-derived exokine CXCL4, is a critical factor in rejuvenating brain ageing and cognitive impairment by attenuating neuroinflammation. Our transcriptomic analysis indicated that 3 protocadherin gamma (Pcdhg) members (Pcdhga10, Pcdhgb4, and Pcdhgb5) were prominently upregulated by PF4 overexpression. This study aims to investigate whether PF4 plays a protective role in the pathogenesis of Parkinson's disease models and explore its underlying molecular mechanism by regulating Pcdhg and its downstream Pyk2. Pcdhg interacts and blocks Pyk2 autophosphorylation (p-Pyk2) and activation. Present study indicated that MPTP treatment decreased Pcdhg while increased p-Pyk2, p-NF-kB, IL-1β, TNF, and phosphorylated-synuclein in Substantia nigra pars compacta (SNc). Both systemic administration of PF4 via the tail vein and local overexpression of lentiviral PF4 administration increased Pcdhg, decreased p-Pyk2, p-NF-kB, IL-1β, TNF, and p-synuclein. PF4 also ameliorated the compromised behavioral activity, neuroinflammation, and neurodegeneration in MPTP injected mice PD model. This study also showed that Pcdhg induced by PF4 was mainly expressed in microglia, whereas Pyk2 was expressed in neurons and microglia. Pcdhg was a transmembrane cell adhesion molecule and microglial Pcdhg may contact neurons through extracellular matrix and activate neuronal Pyk2 activation. This study also showed that Pcdhg induced by PF4 was mainly expressed in microglia, whereas Pyk2 was expressed in neurons and microglia. Pcdhg was a transmembrane cell adhesion molecule and microglial Pcdhg may contact neurons through extracellular matrix and activate neuronal Pyk2 activation. Pyk2 inhibitor PF-562271 administration decreased Pyk2, restored the compromised behavioral activity, neuroinflammation, and dopaminergic cell death in MPTP-injected mice. This study demonstrates that blood-borne PF4 prevents neuroinflammation and neurodegeneration in PD models by inducing Pcdhg expression and subsequently blocking Pyk2 activation. This finding highlights that Pcdhg/Pyk2 axis was a key protective molecular mechanism of PF4 in PD and the Pcdhg-Pyk2 pathway could serve as a potential drug target for PD interventions.