The human liver mediates whole-body metabolism, systemic inflammation and responses to hepatotropic pathogens. Hepatocytes, the most abundant cell type of the liver, have critical roles in each of these activities. The regulation of metabolic pathways, such as glucose metabolism, lipid biosynthesis and oxidation, influences whole-organism functionality. However, the immune potential of the liver in general and hepatocytes in particular is also determined by metabolic ability. The major shifts in cellular metabolism required to drive activity in immune cells are now well-described. Given the unique functions of hepatocytes in systemic metabolism and inflammation, and their ability to mediate local antiviral innate immunity, the metabolic shifts required to facilitate these activities are likely to be complex and challenging to define. In this review, we explore what is known about the complex metabolic rewiring required for hepatocytes to respond appropriately to viral infection. We also discuss how viruses can manipulate hepatocyte metabolism to facilitate infection.