Cassia obtusifolia (CO) has been traditionally used in Korea to treat eye inflammation, photophobia, and lacrimation. However, the regulatory effect and molecular mechanism of CO in intestinal inflammation has not been understood. In this study, we investigate the protective effect of CO in dextran sulfate sodium (DSS)-induced colitis. CO reduced clinical signs of DSS-induced colitis, including body weight loss, shortened colon length, and increased disease activity index. The results show that CO significantly suppressed the levels of interleukin (IL)-6 and expression of cyclooxygenase-2 in DSS-treated colon tissues. Additionally, we observed that CO reduced the activation of transcription nuclear factor-κB p65 in DSS-treated colon tissues. Taken together, these findings suggest that CO has improving effects on DSS-induced ulcerative colitis, which may explain its beneficial effect in the regulation of chronic intestinal inflammation.