Although respiratory symptoms are the most prevalent disease manifestation of infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), infection can also damage other organs, including the brain, gut, and liver. Symptoms of liver damage are observed in nearly half of patients that succumb to severe SARS-CoV-2 infection. Here we use human-induced pluripotent stem cell-derived liver organoids (HLOs) to recapitulate and characterize liver pathology following virus exposure. Utilizing single-cell sequencing technology, we identified robust transcriptomic changes that occur in SARS-CoV-2 infected liver cells as well as uninfected bystander cells. Our results show a significant induction of many inflammatory pathways, including IFN-α, INF-γ, and IL-6 signaling. Our results further identify IL-6 signaling as a potential mechanism for liver-mediated activation of circulating macrophages. Display omitted •Stem cell-derived liver organoids (HLOs) are susceptible to SARS-CoV-2 infection•Within HLOs, hepatocyte-like cells mount the strongest inflammatory response•Co-culture of HLOs with macrophages increases the inflammatory response to infection•Infected HLOs secrete IL-6 which promotes macrophage expression of MCP-1 Health sciences; Immunology; Virology; Stem cells research; Transcriptomics.