AbstractAccording to previous studies, oxidative stress is a leading cause of dopaminergic neuron death and may contribute to the pathogenesis of Parkinson's disease (PD). In the current study, we used chromatography of gel filtration to identify a novel peptide (Lignosus rhinocerotispeptide [LRP]) from the sclerotium ofLignosus rhinocerotis(Cooke) Ryvarden. Its neuroprotective effect was evaluated using an in vitro PD model constructed by 6‐hydroxydopamine (6‐OHDA)‐stimulated to apoptosis in PC12 cells. The molecular weight of LRP is determined as 1532 Da and the secondary structure is irregular. The simple amino acid sequence of LRP is Thr‐Leu‐Ala‐Pro‐Thr‐Phe‐Leu‐Ser‐Ser‐Leu‐Gly‐Pro‐Cys‐Leu‐Leu. Notably, LRP has the ability to significantly boost the viability of PC12 cells after exposure to 6‐OHDA, as well as enhance the cellular activity of antioxidative enzymes like superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH‐Px). LRP also lowers the level of malondialdehyde (MDA), decreases the activation performance of Caspase‐3, and reduces 6‐OHDA‐induced apoptosis via inhibition of nuclear factor‐kappa B (NF‐κB) activation. These data indicate that LRP may have the potential to act as a neuroprotective agent.