Sophoridine (SRI), one of the quinolizidine alkaloids, is a new anticancer drug with noticeable antitumor action and lower toxicity. To our knowledge, there is no report about its effect on colitis. Repeated colitis was induced by administration of four cycles of 4% DSS. The severity of colitis was assessed on the basis of clinical signs, colon length and histology scores. Moreover, cecum secretory immunoglobulin A (sIgA) and plasma haptoglobin (HP) were analyzed by enzyme-linked immunosorbent assay and ICAM-1, and macrophage migration inhibitory factor (MIF) gene expression was analyzed by quantitative reverse transcriptase real-time polymerase chain reaction using SYBR Green I. SRI administration significantly attenuated the damage and caused substantial reduction of the rise in plasma HP, and maintained the level of cecum sIgA. SRI inhibited the ICAM-1 gene expression and had no effect on MIF gene expression. In conclusion, for the first time, the activity of SRI on DSS-induced colitis mice was investigated, which suggests that SRI could be an attractive therapeutic option in the treatment of inflammatory bowel disease.