Purpose <p>The objective of this study was to investigate the association between α-synuclein (α-syn) levels in neuron-derived exosomes (NDEs) and the severity of motor and non-motor symptoms in Parkinson's disease (PD) patients, and to evaluate α-syn in plasma NDEs as a potential early diagnostic biomarker for PD.</p> Methods <p>Fifty-five patients with PD and thirty-three healthy controls (HCs) were enrolled in this study. Additionally, various rating scales were utilized to assess the clinical symptom severity of the PD patients. To quantify the levels of α-syn, we employed magnetic particle-based chemiluminescence immunoassays.</p> Results <p>Compared with HCs, plasma NDE α-syn levels were significantly higher (<i>p</i> &lt; 0.001) in the PD group. After false discovery rate correction for multiple comparisons, plasma NDE α-syn levels remained significantly correlated with UPDRS-III, HAMA, MMSE, and SCOPA-AUT scores (all Q &lt; 0.05). Receiver operating characteristic (ROC) curve analysis demonstrated the significance of α-syn in plasma NDEs for diagnosing early-stage PD. The area under the curve (AUC) for α-syn was found to be 0.732 (95% CI: 0.610–0.854, <i>p</i> &lt; 0.01).</p> Conclusion <p>Our study preliminarily found that the α-syn levels in plasma NDEs were modestly correlated with the severity of motor and non-motor symptoms in PD. Additionally, measuring α-syn in plasma NDEs showed potential as an adjunctive biomarker for aiding in the early detection of PD.</p>