Enterotoxigenic E. coli are major causes of traveler's diarrhea as well as endemic diarrhea and stunting in children in developing areas. However a small mammal model has been badly needed to better understand and assess mechanisms, vaccines and interventions. We report a murine model of ETEC diarrhea, weight loss and enteropathy, and investigate the role of zinc on the outcomes. LT=ST producing enterotoxigenic E. coli (ETEC) given to weaned C57BL/6 mice after antibiotic disruption of normal microbiota cause growth impairment, watery diarrhea, heavy stool shedding and mild to moderate intestinal inflammation, the latter worse with zinc deficiency. Zinc treatment promoted growth in zinc deficient infected mice, and subinhibitory zinc reduced expression of ETEC virulence genes cfa1, cexE, sta2 and degP, but not eltA in vitro. Zinc supplementation increased shedding and ileal burden of WT ETEC but decreased shedding and tissue burden of LTKO ETEC. LTKO ETEC infected mice had delayed disease onset and also had less inflammation by fecal MPO assessment. These findings provide a new murine model of ETEC infection that can help elucidate mechanisms of growth, diarrhea and inflammatory responses as well as potential vaccines and interventions.