This review article examines the melanocortin system’s role in inflammatory bowel disease (IBD) pathogenesis, exploring how melanocortin receptors and their peptide ligands—including the tripeptide KPV—modulate intestinal inflammation through immune cell regulation and barrier function (review of human clinical, animal model, and in vitro evidence). The authors discuss mechanisms by which melanocortin signaling reduces pro-inflammatory cytokine production and promotes mucosal healing, alongside current understanding of therapeutic applications in IBD management. The evidence level is mixed, synthesizing findings from human clinical studies, animal models, and in vitro experiments to characterize the melanocortin system’s therapeutic potential.