The combination of doxorubicin (DOX) with sorafenib (SOR) has proven an effective strategy to enhance anti-hepatocellular carcinoma (HCC) efficacy. However, respective in vivo pharmacokinetic profiles and different endocytosis capacities of these two drugs greatly hinder their current application. Herein, the tumor-targeting peptide iRGD decorated lipid-polymer hybrid nanoparticles (NPs) with a shell-core structure were developed for co-delivery of DOX and SOR (DOX+SOR/iRGD NPs). After the drug ratio was optimized, the stabilized DOX + SOR/iRGD NPs were prepared. Through the iRGD-integrin recognition, DOX + SOR/iRGD NPs showed synergistic cytotoxicity, pro-apoptotic ability and enhanced internalization rate in human liver cancer HepG2 cells. In vivo pharmacokinetic result demonstrated that an extended circulation and bioavailability of DOX + SOR/iRGD NPs than free drugs. More importantly, DOX + SOR/iRGD NPs significantly enhanced antitumor efficiency in HCC xenograft mouse models. Overall, this study describes a promising nanoparticulate drug co-delivery strategy to combine clinical anticancer drugs and enhance anti-HCC efficacy. © 2016 Elsevier Inc.