Nowadays drug delivery to the brain remains a challenge, which is mainly due to the complex tight junctions and selective characteristics of the blood–brain barrier. The aim of the study was to fabricate PPD nanocrystals to improve its oral bioavailability and delivery into the brain. Protopanaxadiol (PPD) is a Darma alkanes tetracyclic triterpene with poor solubility (< 50 ng/ml) and high lipophilicity. PPD exhibits strong anti-cancer activity and antidepressant-like effect, whereas its poor aqueous solubility limits its application. In this study, single factor experiment, including various type of solvents and stabilizers, drug concentration, organic/aqueous solvent ratio and stirring time, was used to study their effects on particle size, polydispersity index (PdI), zeta potential and short-term stability. The PPD nanocrystals were prepared using anti-solvent precipitation where d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was optimized as the stabilizer. The formulation was consisting of 0.5 mg/ml drug, PPD/TPGS at 3:1, and Mill-Q water/acetone at 10:1, and particle size, PdI and zeta potential of the PPD nanocrystals were 90.44 ± 1.45 nm, 0.149 ± 0.016 and − 21.2 ± 0.85 mV, respectively. The fabricated nanocrystals were nearly spherical with uniform size distribution observed by transmission electron microscope. Powder X-ray diffraction analysis indicates that PPD was present in a crystalline state in the nanocrystals. In-vitro stability study showed that PPD nanocrystals can be stabilized at 4 °C for one month. In in-vitro dissolution experiment, more than 70% PPD could be rapidly released from nanocrystals within 3 min in 0.2% (w/v) sodium lauryl sulfate at 37 ± 0.5 °C. After oral administration, PPD nanocrystals were absorbed quickly into plasma with a T_max of 0.70 h, and the plasma C_max values of PPD nanocrystals were 4.75-fold higher than that of the physical mixture. Oral bioavailability of PPD nanocrystals (AUC_all) was 18.1-fold superior than the physical mixture. Interestingly, there was about 1 h delay for PPD to reach to T_max in the brain than that in the plasma, which was eliminated slowly than those in the plasma. The results suggested that PPD was rapidly absorbed into plasma, then transported across the BBB and eliminated in the brain slowly. The intracerebral C_max values of PPD nanocrystals were 2.42-fold higher than that of the physical mixture. In summary, the small-sized PPD nanocrystals may be a potential oral delivery system to enhance PPD's poor bioavailability and its delivery into the brain for neurodegeneration disease and brain cancer therapy.