Background Parkinson disease (PD) is a serious neurodegenerative disease with high increasing rate. Exosomes, carrying numerous biological materials including proteins and lipids, function as crucial players in multiple diseases including PD. Methods Exosomes were isolated from serum samples of PD patients and healthy people, which was validated through transmission electron microscope (TEM) image and protein expression detection of cluster of differentiation protein 9 (CD9) and tumor susceptibility gene 101 protein (TSG101) (exosome markers) via western blot assay. Differentially expressed proteins (DEPs) in serum exosomes were identified through iTRAQ‐LC‐MS/MS. DEPs were annotated and analyzed by Gene Ontology (GO) and KEGG Pathway databases. Protein‐protein interaction networks of these DEPs were established through STRING database. Results A total of 42 DEPs (24 up‐regulated, 18 down‐regulated) were identified in serum exosomes of PD patients versus healthy control group. GO‐biological_process analysis showed that most of DEPs were involved in the regulation of immune system process, vesicle‐mediated transport, response to stress and signal transduction. Moreover, some crucial proteins (e.g. antichymotrypsin (SERPINA3) and hemopexin (HPX)) associated with the pathology of PD were identified through interaction analysis. Western blot and ELISA assays further validated that SERPINA3 and HPX were highly expressed and phospholipid transfer protein (PLTP) was low expressed in serum exosomes of PD patients versus control group. Conclusion Proteomics analysis for serum exosomes of PD patients and healthy people could provide some potential biomarkers and vital information of intercellular communication and pathogenic mechanisms in PD.