Avasimibe, a cholesterol-lowering drug with proven safety in clinical trials, has also been repositioned as an anticancer agent in various preclinical investigations. A study from our group reported that hypercholesterolemia promotes hepatocellular carcinoma (HCC) cell survival and impairs the cytotoxic effect of sorafenib, a kinase inhibitor. In the present study, we demonstrate that under hypercholesterolemic conditions, the anticancer efficacy of sorafenib in HCC is enhanced by co-treatment with avasimibe. To elucidate the role of hypercholesterolemia in sorafenib efficacy, both in vitro and in vivo models of HCC were used. In vitro, co-treatment with both drugs synergistically inhibited HCC cell viability and induced cell death under both normal and hypercholesterolemic conditions. At the molecular level, the downregulation of extracellular signal-regulated kinase signaling and the induction of endoplasmic reticulum stress are likely to contribute to the combinatorial cytotoxic effect of sorafenib and avasimibe in vitro. In mice fed on a high-cholesterol diet, the efficacy of sorafenib was restored by co-administration of avasimibe. Collectively, these findings suggest that the reduction in sorafenib efficacy is due to a hypercholesterolemic phenotype that can be restored by avasimibe co-treatment, with implications for treatment strategy.