Background <p>The clinical diagnosis of multiple system atrophy (MSA) mainly depends on imaging examinations, and the misdiagnosis rate is high due to its similar symptoms to Parkinson’s disease (PD).</p> Objectives <p>This study aimed to identify a non-invasive indicator assisting in discriminating MSA and PD and predict the development of MSA.</p> Materials and methods <p>This study enrolled 127 PD patients, 62 MSA patients, and 78 healthy individuals and collected their serum samples. The serum miR-451 levels were analyzed by PCR. The severity of MSA patients was assessed by the Unified Multiple System Atrophy Rating Scale-II (UMSARS-II). The outcomes of MSA patients were evaluated from the perspectives of cognitive function and motor symptoms.</p> Results <p>Significant upregulation of miR-451 was observed in PD and MSA patients, and MSA patients showed higher serum miR-451 levels. Increasing serum miR-451 levels diagnosed PD and MSA patients from healthy individuals and could discriminate MSA patients from PD patients. miR-451 was positively correlated with UMSARS-II and SCOPA-AUT scores and showed a negative correlation with the MMSE score. MSA patients with motor symptoms and cognitive dysfunction showed higher serum miR-451 levels, and miR-451 was identified as a risk factor predicting the occurrence of cognitive dysfunction and motor symptoms.</p> Conclusion <p>Serum miR-451 can serve as a biomarker for screening MSA and predicting disease development.</p>