ETHNOPHARMACOLOGICAL RELEVANCE: Parkinson's disease (PD) is one of the most common neurodegenerative disorders, yet effective therapeutic options remain limited. Dendrobium huoshanense (DH), a medicinal and edible herb mainly distributed in Ta-pieh Mountains of Central China, has been used to treat disorders of consciousness and chronic nervous diseases in the local hospital for thousands of years. Erianin, a bioactive bibenzyl compound isolated from DH, has emerged as a potential neuroprotective agent due to its anti-inflammatory and antioxidant properties. AIM OF THE STUDY: This study aimed to investigate the neuroprotective effects of Erianin in the treatment of PD and the underlying mechanisms, particularly focusing on inflammation and oxidative stress, through both in vivo and in vitro models. MATERIALS AND METHODS: A 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model was employed. The protective effects of Erianin were evaluated through neurobehavioral tests, immunohistochemistry, immunofluorescence, Nissl staining, serum biochemical tests, and Western blotting. The role of Erianin in modulating the NF-κB/NLRP3 pathway was investigated in lipopolysaccharide (LPS)-stimulated BV-2 microglia cells. RESULTS: Erianin significantly alleviated MPTP-induced motor deficits, reduced neuroinflammation, and reversed abnormal secretion of inflammatory and oxidative stress factors in the serum. Additionally, Erianin suppressed the gene expression of NOD-like receptor protein 3 (NLRP3) and tyrosine hydroxylase (TH) in the striatum of PD mice. And, Erianin inhibited the activation of the NF-κB/NLRP3 pathway, decreased the production of oxidative stress factors, and reversed the secretion of inflammatory mediators in LPS-stimulated BV-2 microglia cells. CONCLUSION: Erianin exerts neuroprotective effects in Parkinson's disease primarily by inhibiting the NF-κB/NLRP3 signaling pathway. These findings suggest that Erianin holds promise as a potential therapeutic candidate for the treatment of PD.