Hepatocellular carcinoma (HCC) causes the third highest mortality worldwide. Liver ablation, surgery, and embolization are conventional methods for treatment. However, these methods have limitations. To overcome these issues, nanomedicines have potential due to their high stability, high drug load capacity, and controlled release. Thus, we prepared quercetin-loaded polylactic-co-glycolic acid (PLGA) nanoparticles coated with folic acid-chitosan (QPCF-NPs) to improve drug delivery and targetability applications of quercetin for the treatment of HCC. We prepared QPCF-NPs by solvent evaporation and coated them with chitosan-folic acid (CS-FA). QPCF-NPs were examined using Fourier-Transform infrared (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X-ray diffraction (XRD). In addition, the drug release rate and cytotoxicity were studied. Moreover, in vivo HCC studies such as histopathology and biochemical parameters were conducted. Subsequently, QPCF-NPs with a spherical shape and an average size of 200–290 nm have been demonstrated to have formed by FTIR, XRD, SEM, and TEM. Further, we observed sustained drug release from QPCF-NPs compared to quercetin. Cellular cytotoxicity showed significant inhibition in the HEPG2-cell line with QPCF-NPs treatment. Biochemical estimate and oxidative stress regulation were considerably more regulated in the treatment groups than the HCC group in a dose-dependent way after subcutaneous administration of QPCF-NPs. ELISA of interleukin and caspase-3 demonstrated the anticipated results in comparison to the carcinogen control group. Compared to earlier preparations, the QPCF-NPs generated demonstrated better drug targetability and potency for treating HCC.