Intestinal disorders and colitis affect millions of humans and food-animals world-wide. Antimicrobial peptides (AMPs) and their broad-spectrum antimicrobial activity represent a valuable potential therapeutic solution. Specifically, the potent pig-originated protegrin-1 (PG-1) has previously been shown to reduce the pathological effects of chemically induced digestive tract inflammation (colitis) along with modulation of immune responses and tissue-repair. This study aimed to extend these findings by investigating the potential protective effects of PG-1 on pathogen-induced intestinal colitis. We found that oral administration of PG-1 reduced Citrobacter rodentium intestinal infection in mice evidenced by; reduced histopathologic change in the colon, prevention of body weight loss, milder clinical signs of disease, and ultimately more effective clearance of bacterial infection relative to challenged mice. Additionally, PG-1 treatment altered the expression of various inflammatory mediators during infection to resolve inflammation and re-establish intestinal homeostasis. Interestingly, PG-1 administered in its mature form was most effective relative to the pro-form (ProPG-1).