Hepatocellular carcinoma (HCC), a common deadly malignancy, requires novel therapeutic strategies to improve the survival rate. Combining chemotherapy and gene therapy is a promising approach for increasing efficiency and reducing side effects. We report on the design of highly specific lipid nanoparticles (LNPs) encapsulating both the chemotherapeutic drug, sorafenib (SOR), and siRNA against the midkine gene (MK), thereby conferring a novel highly efficient anticancer effect on HCC. The LNPs were modified with a targeting peptide, SP94, which is selective for hepatic cancer cells (HCCs), thus permitting the specific delivery of the payload. MK-siRNA increased the sensitivity of HCCs, HepG2, to SOR (IC50 for SOR+MK-siRNA: 5 ± 1.50 μM compared to 9 ± 2.20 and 17 ± 2.60 μM for SOR+control siRNA and MK-siRNA, respectively). The selectivity was confirmed by cellular uptake, cytotoxicity, and gene-silencing studies in HCCs, HepG2, and Hepa 1–6, compared to other cancerous cells, HeLa, and normal cells, FL83B. The use of a novel pH-sensitive lipid, YSK05, increased the cytotoxic and gene knockdown efficiencies and limited extracellular drug release. The nanoparticles were also compatible with serum and showed no aggregation after long storage. The efficient and specific codelivery system reported here is a highly promising strategy for the treatment of HCC.