Crocodylians engage in conspecific territorial disputes that often result in serious injuries that heal rapidly and without infection despite the fact that these animals live in aquatic habitats rich in potentially infectious microbes. We used RNA-seq to characterize the hepatic response of American alligators (Alligator mississippiensis) to acute inflammation and infection. We observed difference in gene expression, relative to uninfected control animals, at 2 and 24 hrs post-infection. Two hours after the experimental infection, we measured increased expression of many genes that were mediators of the inflammatory reaction. The upregulated functional gene pathways at 2-hr post-infection included primarily cytokine production and signaling, while the pathways at 24 hrs involved increased expression of genes that coded for immunomodulatory proteins. Some of the differentially expressed genes at 24 hrs coded for protein products that inhibit the immune response, which indicated a complex host defense response tightly regulated to prevent prolonged stimulation that could result in tissue damage to the host organism. The results of this study show the rapid response of innate immunity and the moderation of this response at 24 hrs.