Liver cancer is one of the leading causes of cancer mortality worldwide. Inspired by the biological structure and function of low-density lipoprotein (LDL), in this study, an ApopB-100 based targeted lipid nanoparticles was synthesized to improve the therapeutic efficacy in liver cancer treatment. The biological composition of ApopB is similar to LDL which can effectively increase the targeting efficiency of nanoparticles in LDL receptor (LDLR)-overexpressed liver tumors. We have demonstrated that the co-administration of sorafenib (SRF) and Dihydroartemisinin (DHA) could exhibit synergistic anticancer effect in HepG2 liver cancer cells. DHA produced excessive cellular reactive oxygen species (ROS) and induced greater apoptosis of cancer cells. LDL-based SRF/DHA-loaded lipid nanoparticles (LD-SDN) showed remarkable decrease in the cell viability compared to that of either of single drug treated cancer cells. Combination of SRF+DHA resulted in predominant SubG1 proportion of cells. LD-SDN exhibited the highest SubG1 (%) of cells compared to that of any of the individual drugs. Most importantly, robust antitumor response and delayed tumor growth was observed for LD-SDN treated xenograft tumor model. Ki67 proliferation index of LD-SDN (22.1 ± 5.6%) is significantly lesser compared to that of either control (86.2 ± 6.9%) or SRF (75.4 ± 4.89%) or DHA (69.4 ± 6.9%). These data provide strong evidence that LDL-mimetic lipid nanoformulations could be utilized as a biocompatible and tumor targeted platform for the delivery of multiple anticancer drugs in cancer treatment.