Purpose: In spite of its enhanced efficacy and reduced side effects in clinical hepatocellular carcinoma (HCC) therapy, the therapeutic efficacy of antitumor angiogenesis inhibitor sorafenib (SFB) is still restricted due to short in vivo half-life and drug resistance. Here, a novel SFB-loaded dendritic polymeric nanoparticle (NP-TPGS-SFB) was developed for enhanced therapy of HCC. Methods: NP-TPGS-SFB was fabricated by encapsulating SFB with biodegradable dendritic polymers poly(amidoamine)-poly(γ-benzyl-L-Glutamate)-b-D-α-tocopheryl polyethylene glycol 1000 succinate (PAM-PBLG-b-TPGS). Results: NP-TPGS-SFB exhibited excellent stability and achieved acid-responsive release of SFB. It also exhibited much higher cellular uptake efficiency in HepG2 human liver cells than PEG-conjugated NP (NP-PEG-SFB). Furthermore, MTT assay confirmed that NP-TPGS-SFB induced higher cytotoxicity than NP-PEG-SFB and free SFB, respectively. Lastly, NP-TPGS-SFB significantly inhibited tumor growth in mice bearing HepG2 xenografts, with negligible side effects. Conclusion: Our result suggests that NP-TPGS-SFB may be a novel approach for enhanced therapy of HCC with promising potential.