<p>Inflammatory bowel disease (IBD), particularly ulcerative colitis (UC), remains a major global health challenge characterized by chronic, relapsing inflammation of the colonic mucosa. Although conventional pharmacotherapies, including corticosteroids and mesalamine are widely used for disease management, their long-term efficacy is often limited by systemic adverse effects, treatment resistance and reduced patient responsiveness. Consequently, growing attention has been directed toward plant-derived bioactive compounds owing to their multi-target therapeutic potential and distinct structural mechanisms. This review highlights the pharmacological potential of <i>Gossypium barbadense</i> L. (Egyptian cotton) root extract as a potential phytotherapeutic candidate for the management of colitis. We summarize current evidence regarding the molecular mechanisms through which its major phytochemical constituents, particularly gossypol and related polyphenolic compounds that modulate inflammatory and oxidative stress pathways. The principal mechanisms include inhibition of NF-κB and COX-2 signaling, enhancement of endogenous antioxidant defense system, preservation of intestinal epithelial barrier integrity and restoration of immune homeostasis. In addition, the immunomodulatory and redox-regulating properties of <i>G. barbadense</i> phytoconstituents are discussed in the context of intestinal inflammation. Furthermore, this review integrates recent advances in network pharmacology to elucidate the multi-component, multi-target interactions underlying the therapeutic effects of <i>G. barbadense.</i> By consolidating current preclinical evidence and computational pharmacology approaches, this review highlights the potential of <i>G. barbadense</i> root as a prospective source of novel therapeutic agent for IBD while identifying key knowledge gaps that should be addressed before clinical translation.</p> Graphical abstract <p></p>