Ulcerative colitis (UC) is a chronic, relapsing form of an inflammatory bowel disease characterized by epithelial barrier dysfunction, immune dysregulation, and gut microbiota imbalance. Despite advances in immunosuppressive and biologic therapy, shortcoming in barrier repair and long-term remission indicate that new treatments are required. The present study aimed to determine the contribution of protein-peptide complexes to the protection against the disruption of the barrier and colonic stress in UC. It seeks to review the mode of action, pharmacokinetic limitations, and therapeutic benefits that may be gained from using peptides as the intervention rather than using the conventional techniques. A literature review and synthesis of recent data on molecular pathophysiology, clinical pharmacology, and advances in drug delivery was performed. Mechanistic models of epithelial regeneration, immune cell targeting, and reconstitution of the microbiome were summarized. Protein-peptide complexes showed broad ranges of effect including epithelial healing, immunosuppression, and microbiota control. Improvement in the tight junction value and the epithelial proliferation by GLP-2 analogs and AMP conjugated the peptides. Combined decrease in pro-inflammatory cytokines (TNF-α, IL-13, IL-17) by cell-penetrating peptides and IL-pathway inhibitors was seen. Hybrid immunomodulatory peptides for immune promotion, regulation of inflammatory macrophage, and Th1-biased immunomodulation of naïve T cells were assessed. Gut-targeted nano-carrier and pH-responsive systems were shown to enhance bioavailability and site-specific delivery of peptide. Co-delivery of peptides and biologics resulted in enhanced clinical scores in preclinical UC models. Protein-peptide complexes are a potential class of bioactive molecules, which could tackle fundamental pathophysiological derangements in UC. Their accuracy to target, low systemic toxicity, and potential for mucosal healing place them among the next generation of therapeutics. On-going translational efforts should combine peptide engineering, nanotechnology, and patient stratification for maximum clinical impact in UC management.