Objective Mouse models of ulcerative colitis (UC) were established with sodium dextran sulfate (DSS) and 2,4,6-trinitrobenzene sulfonic acid ( TNBS) to compare the differences in clinical symptoms, pathological lesions and colonic flora. Methods Thirty male C57BL/ 6 mice were randomly divided into a control group, DSS group and TNBS group. The modeling period was 7 days. Clinical symptoms, including body weight and fecal occult blood, were monitored daily. The colon was harvested at the end of modeling for histopathological diagnosis, and 16S rDNA sequencing technology was used to detect the bacterial composition of the colon contents. Results The clinical result showed that DSS induced diarrhea three days after treatment, fecal occult blood was positive, and body weight was decreased on the fifth day. TNBS treatment decreased body weight on the second day, soft and loose stools were observed from the first to the fourth day, and fecal occult blood was positive. At necropsy, the colon weight in both model groups was increased, whereas the colon in the DSS group was significantly shorter. Histopathologically, the ulcer foci in the colon exhibited a damaged histological structure, and the nearby crypts were dilated in the DSS group, whereas residual crypts accompanied by obvious cell proliferation were observed in the ulcer foci of the TNBS group. The characteristics of colon flora disturbances in the two model groups were different. Compared with the control group, the abundances of Tenericutes and Cyanobacteria were not significantly altered in the DSS group but were increased in the TNBS group (P<0.05). The abundance of Acidobacteria was unchanged in the DSS group but significantly decreased in the TNBS group ( P< 0.05 ). The abundance of Actinobacteria and Lactobacillus was significantly decreased in the DSS group but unchanged in the TNBS group (P<0.05). The abundance of Bacteroidetes was significantly increased in the DSS group but decreased in the TNBS group (P<0.05). Conclusions The UC models induced by DSS and TNBS / ethanol showed similar characteristics in clinical symptoms, pathological changes in colon tissue and intestinal microflora structure, but the two models also exhibited distinct characteristics. The result provide a theoretical reference for animal model selection.