Intestine barrier disruption and bacterial translocation can contribute to sepsis and multiple organ failure， leading causes of mortality in burn-injured patients. In addition， findings suggest that ethanol (alcohol) intoxication at the time of injury worsens symptoms associated with burn injury. We have previously shown that interleukin-22 (IL-22) protects from intestinal leakiness and prevents overgrowth of gram-negative bacteria following ethanol and burn injury， but how IL-22 mediates these effects has not been established. Here， utilizing a mouse model of ethanol and burn injury， we show that the combined insult results in a significant loss of proliferating cells within small intestine crypts and increases Enterobacteriaceae copies， despite elevated levels of the antimicrobial peptide lipocalin-2. IL-22 administration restored numbers of proliferating cells within crypts， significantly increased Reg3β， Reg3γ， lipocalin-2 AMP transcript levels in intestine epithelial cells， and resulted in complete reduction of Enterobacteriaceae in the small intestine. Knockout of signal transducer and activator of transcription factor-3 (STAT3) in intestine epithelial cells resulted in complete loss of IL-22 protection， demonstrating that STAT3 is required for intestine barrier protection following ethanol combined with injury. Together， these findings suggest that IL-22/STAT3 signaling is critical to gut barrier integrity and targeting this pathway may be of beneficial clinical relevance following burn injury.