Epidemiologic studies suggest a relationship between early weaning and the incidence of inflammatory bowel disease. Herein, we addressed the question whether bovine colostrum, the first milk produced by mammals, is able to prevent dextran sulfate sodium (DSS)-induced colitis in mice. Prior to induction of colitis with 5% DSS, Naval Medical Research Institute mice were fed bovine colostrum [BV-20 or 200 mg/kg body weight (BW)], BSA (20 mg/kg BW), or water (100 μL) daily by oral gavage for 2 wk. The clinical severity of colitis was determined by scoring changes in BW and colon length reduction. Following 2 wk of observation, the colons were removed for histologic and immunohistochemical evaluation of inflammation. Flow cytometric phenotyping of leukocyte subsets was performed from peripheral blood, mesenteric lymph nodes, and spleens. Administration of bovine colostrum improved the clinical and histologic severity of colorectal inflammation. Compared with BSA-fed and water-fed controls, BV-20 pretreated mice had significantly less severe weight loss and decreased colon shortening. Beneficial effects were accompanied by redistribution of immunoregulatory, peripheral and splenic γδ TCR(+) cells, and CD11b(+)Gr1(+) cells. Higher colostrum doses did not affect disease activity. In summary, prophylactic administration of colostrum improved clinical symptoms of colorectal inflammation in a well-established mouse model of DSS-induced colitis. Further investigations will target the underlying immunomodulatory mechanisms to our approach.