Liver fibrosis is the result of an exacerbated wound-healing response associated with chronic liver injury. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and frequently requires liver transplantation. The host immune response has an important role driving fibrosis deposition by activating hepatic stellate cells (HSCs). Interleukin-22 (IL-22) is a cytokine that plays a key role in promoting antimicrobial immunity and tissue repair at barrier surfaces. Data from literature suggest that IL-22 has a protective role in the liver by reducing fibrosis in some pathological conditions, however the results are contradictory. This review highlights current knowledge of IL-22’ role in chronic liver injury, as well as its therapeutic potential for the treatment of chronic liver injury.