Resveratrol (RES), a non-flavonoid polyphenol extracted from a wide variety of plants, possesses neuroprotective activity for the treatment of Parkinson’s disease (PD). However, the poor water solubility of RES results in low oral bioavailability, which causes low exposure of RES in the blood and brain, and limits its anti-Parkinsonian efficacy and clinical application. In this study, a nanocrystal formulation of RES (RES-NCs) was developed to improve its solubility and oral bioavailability and thus to treat PD. The RES-NCs were fabricated using an anti-solvent precipitation approach where hydroxypropyl methylcellulose (HPMC) was optimized as the stabilizer. The obtained RES-NCs had a particle size of 222.54 ± 1.66 nm with a PDI of 0.12 ± 0.03, and the RES-NCs exhibited a fast dissolution rate in vitro. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) results demonstrated that the RES was maintained in the crystalline state in the fabricated nanocrystals. Molecular dynamics simulation of RES and HPMC exhibited an interaction and binding energy of -68.09 kJ/mol and -30.98 ± 0.388 kJ/mol, respectively with van der Waals interactions in the spontaneous binding. The cellular uptake and permeability of RES-NCs were much higher than those of the raw RES in Madin-Darby Canine Kidney (MDCK) cells (p<0.01). In addition, the RES-NCs afforded a significant neuroprotective effect against 1-methyl-4-phenylpyridinium ion (MPP+)-induced damage in SH-SY5Y cells. Meanwhile, the zebrafish embryos and larvae treated with RES-NCs did not show any obvious toxic effects during the entire experiment. When RES-NCs were orally administrated to rats, the drug was absorbed quickly and a maximum plasma concentration of 2.97 ± 0.46 μg/ml was reached in 2.11 ± 0.05 h. Compared to the unformulated RES, the Cmax and AUC0-24 h of RES-NCs were increased nearly 3.09- and 3.52-fold, respectively, indicating that the RES-NCs could effectively enhance RES oral absorption. The RES-NCs also resulted in markedly higher brain Cmax and AUC0-24 h values of 0.26 ± 0.02 μg/g and 2.61 ± 0.21 μg·h/g, respectively in comparison with the unformulated RES. Most importantly, the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mice had notably improved behavior disorder, reversed dopamine depletion, and attenuated the decrease in the levels of dopamine and its metabolites during one-week post-observation after treatment with RES-NCs. In summary, RES-NCs are a potential oral delivery system to improve RES’s poor bioavailability and its delivery into the brain for the treatment of PD.