Bexarotene (Targretin®) is a synthetic retinoid that selectively activates the retinoid X receptor subfamily of retinoid receptors and exhibits potent anti-tumor activity. However, the poor solubility and bioavailability limit its application. The main aim of this study is to investigate the potential of oral and parenteral nanocrystals in enhancing the bioavailability of bexarotene. In this work, the orthogonal design was used to screen the optimum stabilizers and precipitation-combined microfluidization method was employed to obtain the optimal nanocrystals. According to DSC, X-ray diffraction analysis and Raman examination, the nanocrystals were still in crystalline state after the preparation procedure. By reducing the particle size, the in vitro dissolution rate of bexarotene was increased significantly. The in vivo test was carried out in rats and pharmacokinetic parameters of the bexarotene solution and bexarotene nanocrystals were compared after gavage and intravenous administration. The higher AUC and lower Cmax indicated that oral bexarotene nanocrystals significantly increased the bioavailability of bexarotene and decreased its side effects. Compared to the oral nanocrystals, the intravenous nanocrystals cut losses and increased bioavailability because of the absence of first pass effect and enterohepatic circulation.