We profile changes in the intrahepatic transcriptomes of HAV-infected Mavs-/- and Ifnar1-/- mice, and investigate the role played by transcriptional activation of IRF3 in the pathogenesis of acute hepatitis A. We demonstrate that HAV-mediated hepatocellular apoptosis requires transcriptional activation of IRF3 by phosphorylation at Ser388/399, distinguishing IRF3-dependent HAV liver injury from IRF3-mediated alcohol-related disease, and identify IRF3-responsive genes for which the level of intrahepatic expression correlates closely with the severity of the liver injury. Here, IRF3 is linked to hepatitis A virus infection.