The therapeutic potential of molecular hydrogen (H₂) is emerging in a number of human diseases and in their animal models, including in particular Parkinson's disease (PD). H₂ supplementation of drinking water has been shown to exert disease-modifying effects in PD patients and neuroprotective effects in experimental PD model mice. However, H₂ supplementation does not result in detectable changes in striatal H₂ levels, indicating an indirect effect. Here we show that H₂ supplementation increases gastric expression of mRNA encoding ghrelin, a growth hormone secretagogue, and ghrelin secretion, which are antagonized by the β1-adrenoceptor blocker, atenolol. Strikingly, the neuroprotective effect of H₂ water was abolished by either administration of the ghrelin receptor-antagonist, D-Lys(3) GHRP-6, or atenolol. Thus, the neuroprotective effect of H₂ in PD is mediated by enhanced production of ghrelin. Our findings point to potential, novel strategies for ameliorating pathophysiology in which a protective effect of H₂ supplementation has been demonstrated.