Purpose: Targeted hepatocellular carcinoma therapy was carried out to improve the efficacy of liver cancer treatment. The purpose of this study was to design an N-acetylgalactosamine (NAcGal) modified and pH sensitive doxorubicin (DOX) prodrug (NAcGal-DOX) for the construction of lipid nanoparticles (LNPs). Methods: NAcGal-DOX and sorafenib (SOR) co-loaded LNPs were designed and the synergistic effects were evaluated on human hepatic carcinoma (HepG2) cells in vitro and anti-hepatic carcinoma mice model in vivo. Results: Cellular uptake efficiency of NAcGal modified LNPs was significantly higher than unmodified LNPs. NAcGal modified LNPs showed the most significant inhibition effect among all the samples tested. The results revealed that the LNPs system achieved significant synergistic effects, best tumor inhibition ability and the lowest systemic toxicity. Conclusion: These results proved that the NAcGal conjugated and pH sensitive co-delivery nano-system could be a promising strategy for treatment of hepatocellular carcinoma.