<p>The objective of the project was to create nanoparticles coated with hyaluronic acid and chitosan, which would be loaded with sorafenib tosylate (SF). These nanoparticles were intended to be used for the specific treatment of hepatocellular carcinoma, with the goal of improving the effectiveness of sorafenib-based chemotherapy. The Box-Behnken design yielded an optimal formulation with a particle size of 147.43 ± 1.76&#xa0;nm, an entrapment efficiency of 66.40 ± 0.7%, and a zeta potential of − 11.08 ± 0.6&#xa0;mV. The characterization techniques employed were dynamic light scattering (DLS), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FTIR), and UV–visible spectroscopy. The drug release in a pH 7.4 buffer, when tested in a laboratory setting, conformed to the Higuchi model (with a coefficient of determination, <i>R</i>², equal to 0.954) and exhibited Fickian diffusion (with a value of <i>n</i> less than 0.5). Cytotoxicity assays on HEPG2 cells revealed substantially greater activity (<i>p</i> &lt; 0.05) than free SF. Superior biocompatibility, targeting efficiency, and pharmacokinetics were demonstrated in in vivo investigations conducted on Wistar rats. Therefore, hyaluronic acid–coated chitosan nanoparticles may improve SF delivery and hepatocellular carcinoma therapy.</p> Graphical abstract <p></p>