BACKGROUND Parkinson's disease (PD) is a common age-related neurodegenerative disorder, but effective therapeutic agents for PD remain largely limited. MATERIAL AND METHODS In the present study, we evaluated the beneficial effects and underlying mechanisms of punicalagin (PN) in human neuroblastoma SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA) to mimic PD in vitro. Cell viability was monitored by MTT assay and LDH release assay. Cell apoptosis was assayed by Annexin V-FITC/PI double-staining. Intracellular ROS production was assessed by DCFH-DA staining. The expression levels of protein and mRNA were determined by Western blotting and qRT-PCR analysis, respectively. RESULTS The results showed that pretreatment of SH-SY5Y cells with PN (50, 100, and 200 ?M) prior to exposure to 200 ?M 6-OHDA for 2 h resulted in increased cell viability and decreased cell apoptosis. PN also inhibited excessive oxidative stress in 6-OHDA-treated SH-SY5Y cells. Moreover, PN treatment effectively restored mitochondrial function and enhanced phosphorylation of AMPK. Furthermore, PN blocked 6-OHDA-induced NF-κB activation and IL-1β expression. CONCLUSIONS Our study shows that PN exhibited neuroprotective effects on the 6-OHDA-treated SH-SY5Y cells, thus providing a potential theoretical insight for the clinical application of PN against PD.