In an attempt to understand the neuroprotective effect of Fructus Alpinia oxyphylla (AOE) and to elucidate its underlying mechanism of action, the ethanolic extract of AOE was investigated using zebrafish and PC12 cell models. AOE prevented and restored 6-hydroxydopamine (6-OHDA)-induced dopaminergic (DA) neuron degeneration and attenuated a deficit of locomotor activity in a zebrafish (Danio rerio) model of Parkinson's disease (PD). Treatment with AOE increased the viability of 6-OHDA-treated PC12 cells in vitro in a dose-dependent manner by attenuating cellular apoptosis. However, protocatechuic acid (PCA) and chrysin, two known polyphenol components of AOE, could not reproduce the neuroprotective activity of AOE in the PD zebrafish or PC12 cell models. A mechanistic study found that the protective effect of AOE against 6-OHDA-induced neuronal injury involved anti-inflammatory action (down-regulation of gene expression of IL-1β and TNF-α) and anti-oxidative action (inhibition of NO production and iNOS expression in PC12 cells). Moreover, the PI3K-AKT pathway might be part of the mechanism of neuroprotection of AOE. The results of this research are expected to provide a scientific rationale for the use of AOE in the treatment of PD. However, it is important that the active components that contribute to the neuroprotective action of AOE are identified and characterized.