Acute liver failure results from severe hepatic injury and can lead to neurological dysfunction known as hepatic encephalopathy (HE). Thrombospondin-1 can contribute to HE by increasing cerebral edema and microglia activation in the azoxymethane (AOM) mouse model. CD47 is a receptor for TSP1 and can directly modulate inflammation in numerous disease states. However, the role of CD47 in the progression of HE is currently unknown. Therefore, the aim of this study was to assess the role of CD47 in liver and brain pathology in the AOM mouse model of HE. C57Bl/6 or CD47 knockout (CD47) were administered AOM to induce acute liver failure and HE. Liver damage was evaluated by measuring serum transaminases and histological assessment. Neurological function was determined by evaluating the time taken to reach coma (loss of all reflexes), cerebral edema, and microglia activation. CD47 signaling, and downstream signaling pathways, were assessed by real-time PCR, western blotting, immunofluorescence, and immunohistochemistry. AOM-treated mice had increased expression of CD47 in the liver, cortex, hippocampus, and cerebellum when compared to vehicle-treated mice. CD47 AOM-treated mice had reduced liver injury and apoptosis when compared to wildtype AOM-treated mice. A slower degree of neurological decline and less cerebral edema were observed in CD47 mice compared to wildtype AOM-treated mice. This was associated with decreased microglia proliferation and increased SOD1 expression in CD47 mice compared to wildtype AOM-treated mice. These findings support that CD47 signaling exacerbates AOM-induced acute liver failure and HE by inducing hepatic cell death, cerebral edema, and microglia activation.