Objective To explore the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor and DPP-4 inhibitor in combination with sulfasalazine (SASP) on the progression of ulcerative colitis in mice. Methods Thirty male BALB/c mice were randomly divided into five groups: control group, ulcerative colitis group, DPP-4 inhibitor group, SASP group and the combined group. 5% dextran sulfate sodium (DSS) was used to induce the mice models of ulcerative colitis. From the first day of constructing the models, the control group and ulcerative colitis group underwent 0.5% carboxymethylcellulose (CMC) gavage, while DPP-4 inhibitor group, SASP group and the combined group received sitagliptin, SASP, or both respectively. All these treatments were conducted once a day for six days. Body weight, characteristics of stool, and the presence of blood in the stools were measured every day to assess the disease activity index (DAI) scores. Six days later, all mice were sacrificed. The colon length, colon pathological changes and serum GLP-2 levels were detected respectively. Results Compared to the ulcerative colitis group, the clinical symptoms and the colon pathological lesion in all three treatment groups were significantly attenuated, the DAI scores were significantly lower (P<0.05), the colons were significantly longer (P<0.05); serum GLP-2 levels of the DPP-4 inhibitor group and the combined group were significantly higher (P<0.01). In addition, compared to the DPP-4 inhibitor group, the DAI scores were significantly lower (P<0.01) and the colons were significantly longer (P<0.01). Conclusion DPP-4 inhibitor could effectively treat UC in mice. DPP-4 inhibitor combined with SASP is more effective in treating UC than either agent alone.