Hepatocellular carcinoma (HCC) treatments have low efficacy, as FDA‐approved drugs including sorafenib extend patient survival by three months. We sought to identify novel druggable targets for use in combination with sorafenib to increase its efficacy. We implemented a genetic screening paradigm using an overexpression library of 43 genes. We administered this library in the context of liver injury and treated mice with vehicle or sorafenib and determined the genetic drivers of each tumor. Mice injected with the screening library developed HCC clones containing MYC cDNA plus various other cDNAs. Treatment with sorafenib resulted in sorafenib‐resistant HCCs that were significantly depleted in NR1H3 cDNA, encoding Liver X receptor (LXR), suggesting that LXR activation is incompatible with tumor growth during sorafenib treatment in vivo. Combination treatment using sorafenib and LXR agonist GW3965 in multiple HCC cell lines and a primary cell line led to enhanced cell death as compared to monotherapy, due to reduced expression levels of cell cycle regulators and increased expression of genes linked to apoptosis. Pathway analysis revealed alterations in metabolic pathways, and we observed upregulation of gluconeogenic regulators and downregulation of glycolytic regulators in sorafenib and combination treatment, and increased regulation of fatty acid synthesis genes in GW3965 and combination treatment. When gluconeogenesis and fatty acid synthesis are reduced using siRNA, cells are resistant to combination therapy. We propose that sorafenib upregulates glucose synthesis and downregulates glycolysis, while GW3965 upregulates fatty acid synthesis. In combination, sorafenib and GW3965 deplete cellular resources required for ATP production, subsequently leading to apoptosis.