The intestinal epithelial cells (IECs) lining the gut serve as a robust defense against ingested toxins and pathogens. Impairment in gut epithelial integrity and barrier function is linked to various diseases. Previous research highlighted the significance of AMPK in regulating intestinal barrier function in the pathogenesis of DSS-induced experimental colitis. To understand AMPK's role in mucosal homeostasis, the impact of AMPK deficiency on enteric infection and colorectal cancer (CRC) was studied. First, we aimed at deciphering its protective role against infectious colitis caused by the natural murine pathogen Citrobacter rodentium, a close relative of the enteropathogenic Escherichia coli. We observed that the bacterial load in the feces during the course of infection, colonic inflammation, or crypt hyperplasia did not differ in Prkaa1fl/fl / Prkaa2fl/fl / Villin-Cre+ mice compared with their littermate floxed controls. These results suggest that AMPK signaling in IECs is dispensable to limit Citrobacter rodentium infection-induced colitis progression. Second, two murine models of CRC were examined: the AOM/DSS model mimicking colitis-associated cancer and a genetic model with an Apc gene knockout, commonly mutated in sporadic CRC in humans. AMPK loss in IECs promoted tumor initiation and growth in the carcinogen-induced CRC model. However, in the genetic predisposition model, AMPK loss showed reduced effect on tumor burden. This suggests AMPK has a dual role in CRC, acting as both a tumor suppressor and promoter based on the stage of tumorigenesis. In summary, these findings emphasize the multifaceted nature of AMPK's involvement in gut health.