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Objective: Accumulation of α‐synuclein (α‐syn) in neurons is a prominent feature of Parkinson's disease (PD). Recently, researchers have considered that extracellular vesicles (EVs) may play an important role in protein exportation and propagation, and α‐syn‐containing EVs derived from the central nervous system (CNS) have been detected in peripheral blood. However, mechanistic insights into CNS‐derived EVs have not been well‐described. Methods: Likely neurogenic EVs were purified from the plasma of PD patients and healthy controls using a well‐established immunoprecipitation assay with anti‐L1CAM‐coated beads. A Prnp‐SNCAA53T transgenic PD mouse model was used to evaluate the neuronal pathology induced by PD‐derived L1CAM‐purified EVs. EV‐associated microRNA (miRNA) profiling was used to screen for altered miRNAs in PD‐derived L1CAM‐purified EVs. Results: PD patient‐derived L1CAM‐purified (likely neurogenic) EVs facilitated α‐syn pathology and neuron loss in Prnp‐SNCAA53T transgenic PD mice. The miRNA, novel_miR_44438, was significantly increased in the PD group, which promoted α‐syn accumulation and neuronal degeneration in a dose‐dependent manner. Novel _miR_44438 directly targets NDST1 mRNA and inhibits the function of heparan sulfate, thus preventing exosome biogenesis and α‐syn release from exosomes. Interpretation: Novel_miR_44438 in PD‐derived L1CAM‐purified EVs inhibits the α‐syn efflux from neurons thereby promoting the pathological accumulation and aggregation of α‐syn. ANN NEUROL 2022;92:230–245 [ABSTRACT FROM AUTHOR]