AbstractDecreased DJ‐1 protein impairs antioxidative activity of neurons and plays an important role in the occurrence of Parkinson's disease (PD). We have previously identified hsa‐miR‐4639‐5p as the post‐transcriptional regulator of DJ‐1. Increased expression of hsa‐miR‐4639‐5p reduced DJ‐1 level and increased oxidative stress leading to neuronal death. Therefore, understanding the detailed mechanisms by which hsa‐miR‐4639‐5p expression is regulated will not only facilitate diagnosis but also inform the pathogenesis of PD. We examined hsa‐miR‐4639‐5 in either the plasma or exosomes derived from the central nervous system (CNS) neurons of PD patients and healthy controls. We showed that CNS‐derived exosomes gave rise to the increased plasma hsa‐miR‐4639‐5p in PD patients, pointing to hsa‐miR‐4639‐5p dysregulation in the brain of PD patients. Using a dual‐luciferase assay and a CRISPR‐Cas9 system, we identified a core promoter of hsa‐miR‐4639 (−560 to −275 upstream the transcriptional starting site) of the gene for myosin regulatory light chain interacting protein. A polymorphism in the core promoter (rs760632 G>A) could enhance hsa‐miR‐4639‐5p expression and increase PD risk. Furthermore, using MethylTarget™ assay, ChIP‐qPCR, and specific inhibitors, we demonstrated that hsa‐miR4639‐5p expression was regulated by HDAC11‐mediated histone acetylation but not DNA methylation/demethylation. Taken together, our study provides evidence that hsa‐miR‐4639‐5p is a potential diagnostic marker and therapeutic target for PD. Interventions targeting hsa‐miR‐4639‐5p might represent a novel therapy to promote healthy aging.