The intestinal mucosa serves as a highly selective barrier that allows the absorption of nutrients and water while restricting microbiota access to tissues. This barrier is compromised in inflammatory conditions such as infectious colitis and inflammatory bowel disease (IBD). In response to mucosal injury, there is a temporal recruitment of leukocytes that crosstalk with epithelial cells to orchestrate repair. Specialized pro-resolving mediators (SPMs) play an important role in the resolution of inflammation and epithelial repair. SPMs actively promote resolution of inflammation by contributing to the clearance of neutrophils, stimulating efferocytosis, and promoting epithelial repair. SPMs have potential to serve as targeted therapeutic agents to be used in adjuvant therapy to promote resolution of inflammation and epithelial repair in chronic inflammatory diseases.