The prevalence of metabolic diseases has become a severe public health problem. Previously, we reported that Interleukin-22 (IL-22) was independently associated with type 2 diabetes mellitus and cardiovascular disease, and could protect endothelial cells from glucose- and lysophosphatidylcholine-induced injury. The activity of IL-22 is strongly regulated by IL-22-binding protein (IL-22BP). The aim of this investigation was to determine the effect of IL-22/IL-22BP axis on glucolipid metabolism. Serum IL-22 and IL-22BP expression in metabolic syndrome (MetS) patients and healthy controls was examined. IL-22BP-knockout (IL-22ra2−/−) and wild-type (WT) mice were fed with control diet (CTD) and high-fat diet (HFD) for 12 weeks. The IL-22 related pathway expression, the glucolipid metabolism, and inflammatory markers in mice were examined. Serum IL-22 and IL-22BP levels were found significantly increased in MetS patients (p < 0.001). IL-22BP deficiency down-regulated IL-22-related pathway, aggravated glucolipid metabolism disorder, and promoted inflammation in mice. Collectively, this work deepens the understanding of the relationship between IL-22/IL-22BP axis and metabolism disorders, and identified that down-regulation of IL-22/IL-22BP axis promotes metabolic disorders in mice.