Objective To evaluate the therapeutic effect and possible mechanism of IL-12 monoclonal antibody (IL-12 mAb) on IL-10 knockout(IL-10-/-) mice and its possible mechanism. Methods Sixteen male IL-10-/- mice of 15 weeks old were randomly divided into control group and IL-12 mAb treatment group. The IL-12 mAb treatment group were given intraperitoneal injection of IL-12 mAb (25 mg/kg, once per week), and the control group was given intraperitoneal injection of 0.2 mL of normal saline. After 4 weeks of intervention, the inflammatory bowel disease activity index (DAI) and HE staining were used to evaluate the intestinal inflammation symptoms and histological changes. The intestinal mucosal permeability test was used to evaluate the intestinal mucosal barrier function of the two groups. The expression of claudin-1 in intestinal mucosa was detected by Western blot analysis. The Th1/Th2 cell balance of intestinal mucosa was evaluated by flow cytometry. The ELISA was used to evaluate IL-13 and tumor necrosis factor alpha(TNF-α) of intestinal mucosal of the two groups. The expression of phosphorylated signal transducer and activator of transcription (p-STAT6) in intestinal mucosa was detected by Western blot nanlysis. Results Three and 4 weeks after IL-12 mAb treatment, the DAI and intestinal inflammation scores of IL-12 mAb treatment group were significantly lower than the control group. At the same time, the intestinal mucosal permeability of IL-12 mAb treatment group was significantly lower than that of the control group, and the expression of claudin-1 in intestinal mucosa was significantly higher than that of the control group. At the same time, IL-12 mAb treatment inhibited the proportion of Th1 cells in the intestinal mucosa and up-regulated the proportion of Th2 cells. In the signal pathway analysis, IL-12 mAb treatment increased the levels of p-STAT6 and IL-13 in the intestinal mucosa and inhibited the level of TNF-α. Conclusion IL-12 mAb effectively alleviates intestinal inflammation in the Crohn's disease animal model and protect the intestinal mucosal barrier, which may be through inhibition of Th1 cell immune response in the intestinal mucosa and up-regulation of STAT6 signaling.