Schisantherin A (SA), a main dibenzocyclooctadience lignan isolated from the fruit of Schisandra chinensis (Turcz.) Baill. (S. chinensis), possesses neuroprotective activity in Parkinson's disease therapy. SA is a poorly water soluble (0.01 mg/ml in water at room temperature) and highly permeable (P_app = 1.7 × 10^− 5 cm/s) active pharmaceutical ingredient belonging to BCS II class. However, the poor water solubility of SA results in low oral bioavailability, which causes low exposure of SA in the blood and brain, and limits its neuroprotective effects and clinical application. The purpose of this work was to prepare SA nanocrystals to improve its dissolution rate and oral bioavailability, therefore to increase the drug concentration in the brain. The anti-solvent precipitation process was optimized by single factor design to determine the effect of each factor on mean particle size, PDI and stability of SA nanocrystals. Needle shaped crystals (~ 160 nm in diameter) with ~ 33% drug loading were generated when 0.25 ml SA in acetone solution (20 mg/ml) was injected quickly into 10 ml of the HPMC E3 solution (0.1%, w/w) with stirring at 1000 rpm/min. DSC and PXRD results demonstrated that SA was in the crystalline state in the fabricated nanocrystals. SA nanocrystals exhibited complete release in 15 min with a remarkable fast dissolution rate, whereas less than 10% SA was dissolved after 1 h for pure SA or physical mixtures groups in in vitro dissolution study. After oral administration of SA nanocrystals to rats (4 mg/kg), the drug was absorbed quickly and a maximum plasma concentration of 9135 ± 799 ng/ml was reached in 1.5 h. Thereafter, the drug was eliminated rapidly where the SA plasma concentration decreased quickly with a t_1/2 of 3.2 h. Compared to SA suspension, the C_max and AUC_0 -24 of SA nanocrystals were increased 7.9- and 6.4-fold, respectively, indicating that formation of the nanocrystals effectively increased drug absorption and improved its oral bioavailability. Moreover, a significant amount of SA was accumulated in rat brain at 515 ng/g after 2 h oral administration, and it was maintained at 274 ng/g after 8 h. And more SA could be delivered into the brain after oral administration of SA nanocrystals than that for SA suspension. This study demonstrated that formulation of nanocrystals is an effective strategy for BCS II natural products with high membrane permeability to enhance their oral absorption and brain delivery.