Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is an immune disorder that causes chronic inflammation of the gastrointestinal tract. There is an unmet need for effective pharmacological treatments as current standard therapies including aspirin derivatives and corticosteroids often fail to control the disease. For a significant portion, 30% or more, of patients, surgical removal of the affected bowel is required at some point in their disease course to address complications of bleeding, infections with sepsis, toxic megacolon among many others. There are also associated severe complications involving many other organs due to the underlying immune mediated reactions. In this study, PEGylated Serp-1 (PEGSerp-1) a modified Myxomavirus-derived serine protease inhibitor that binds and inhibits serine proteases in the coagulation and complement cascades, is evaluated in a pre-clinical model of IBD. Experimental colitis was induced in male C57BL/6J mice by oral administration of dextran sulfate sodium (DSS). In mice with acute colitis induced by exposure to 5% DSS for 6 days, daily treatment with PEGSerp-1 significantly improved survival. When initiation of treatment was delayed by 7 days in this acute colitis model, PEGSerp-1 treatment improved markers of disease severity and significantly reduced inflammation in the colon. PEGSerp-1 is an effective treatment of acute DSS-induced colitis when used as a preventative or delayed treatment.