Recent research studies have shown that the low survival rate of liver cancer is due to drug resistance and metastasis. In the tumor microenvironment (TME), activated hepatic stellate cells (aHSCs) have been proven to favor the development of liver cancer. Hence, the combination therapy dual-targeting aHSCs and tumor cells might be an effective strategy for treatment of liver cancer. In this study, the novel multifunctional liposomes (CAPS-CUR/GA&Gal-Lip) were prepared for co-delivery of curcumin (CUR) and capsaicin (CAPS), in which glycyrrhetinic acid (GA) and galactose (Gal) were chosen as targeting ligands to modify the liposomes (Lip) for dual-targeting liver cancer. To mimic TME, a novel HSCs+HepG2 (human hepatoma cell line) cocultured model was established for the antitumor effect . The results showed that, compared to HepG2 cells alone, the cocultured model promoted drug resistance and migration by upregulating the expression of P-glycoprotein (P-gp) and Vimentin, which were effectively inhibited by CAPS-CUR/GA&Gal-Lip. The efficacy of the antitumor was evaluated by three mice models: subcutaneous H22 (mouse hepatoma cell line) tumor-bearing mice, H22+m-HSC (mouse hepatic stellate cell) tumor-bearing mice, and orthotopic H22 cells-bearing mice. The results showed that CAPS-CUR/GA&Gal-Lip exhibited lesser extracellular matrix (ECM) deposition, lesser tumor angiogenesis, and superior antitumor effect compared with the no- and/or Gal-modified Lip, which was attributed to the simultaneous blocking of the activation of HSCs and inhibition of the metastasis of tumor cells. The dual-targeting method using Lip is thus a potential strategy for liver cancer treatment.