Background: Sorafenib (SRF) is a multiple kinase inhibitor approved for several cancers including hepatocellular carcinoma and advanced renal cell cancer. However, the oral bioavailability of SRF is excessively low (approximately 8.43%) due to its aqueous solubility. Objective: The objective of this study was to prepare sorafenib nanosuspensions (SRF-NSs) to improve dissolution and oral bioavailability with hydrophilic polymers as stabilizers and sodium lauryl sulfate (SLS) as a surfactant. Materials and Methods: SRF-NSs were prepared by combination of ultrasonication and high pressure homogenization technique, followed by lyophilization for storage stability and further processes. To optimize SRF-NSs, the main parameters such as ratios of stabilizers and SLS (w/w), ultrasonication time, homogenization pressure and cycles of high pressure homogenization were investigated. The physicochemical properties of SRF-NSs were evaluated for particle size, polydispersity index and zeta potential. The optimized SRF-NSs were characterized for surface morphology, crystallinity, dissolution in pH 1.2 and pH 6.8, and pharmacokinetics in rats. Results: Hydroxypropyl cellulose (HPC), a water-soluble cellulose ether, was the most efficient hydrophilic polymer in the preparation of nanosuspensions. In particular, SRF-NSs prepared with SRF, Klucel™ HPC EXF and SLS (10:5:1, weight ratio) showed the smallest particle size near 300 nm and low polydispersity index below 0.3 indicating a narrow particle size distribution. The optimized SRF-NSs showed an enhanced dissolution and oral bioavailability of SRF compared with SRF powder due to their reduced particle size and amorphous state conversion. Conclusion: Thus, SRF-NSs could be a promising strategy to enhance the oral bioavailability of SRF.