Hepatocellular carcinoma (HCC) shows low response to most conventional treatment strategies. Therefore, there is an urgent need for new and effective chemotherapies. Nanotechnology gives a dramatic impact on medicine. In this work, paclitaxel loaded nanoparticles (NPs) decorated with bivalent fragment HAb18 F(ab')2 and/or cell penetrating peptide (CPP) were developed and evaluated. NPs were prepared by emulsification-solvent evaporation method and decorated by carbodiimide chemistry. The physicochemical characteristics of NPs (i.e. encapsulation efficiency, particle size distribution, morphology, release in vitro) were investigated. Cellular uptake and accumulation in tumor tissue of NPs were determined. To assess anti-tumor activity of NPs in vitro and in vivo, cell survival assay and tumor regression study were carried out using HCC cell lines (HepG2 and Huh7) and their xenografts. Average particle size of all NPs was between 100 and 200 nm. Drug-loaded NPs possessed spherical morphology and higher encapsulation efficiency. The accumulation of NPs decorated with HAb18 F(ab')2 and CPP depended on dual effects of passive and active targeting. Drug loaded nanoparticles showed cytotoxicity on the tumor cells in vitro and in vivo. NPs decorated with HAb18 F(ab')2 and CPP showed maximization of therapeutic action for targeting and effective endocytosis. These results suggest that the nano-drug delivery system could be a promising candidate with excellent therapeutic efficacy for HCC therapy.