Background: Inflammatory bowel disease (IBD) is a condition in which the gastrointestinal system becomes inflamed for no apparent reason. Its incidence increased during the last few decades. As a result, it's critical to understand how to validate a clinical diagnosis and monitor any progress using a simple procedure. Osteoprotegerin (OPG), which interacts with RANKL, regulates RANK/RANKL signaling. OPG is a decoy receptor for soluble receptor activator of nuclear factor-B ligand (sRANKL), which stimulates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the healing trefoil factor 3 (TFF3), which could be employed as in the diagnosis and follow-up of IBD patients, biomarkers are used. Objectives: The aim of the current work was to evaluate the role of RANKL (sRANKL), OPG, NF-κB , and TFF3 in in the diagnosis of active IBD. Subjects and  methods: Thirty-five newly diagnosed untreated IBD patients and thirty-five healthy controls were included in this study. Patients were then given particular treatment either in the form of cortisone, mesalamin, immunotherapy or infliximab and immunotherapy for 3 months and attend for second visit. OPG, sRANKL, NF-κB and TFF3 levels were estimated by ELISA method using commercial kits in patients before and after treatment and healthy control. Results: Patients with IBD had significantly increased levels of OPG, sRANKL, NF-B, and TFF3 than healthy controls (P =0.0001). After 3 months of treatment, patients' levels of NF-B and TFF3 were significantly lower (p = 0.0001 and 0.03, respectively). Conclusion: The biomarkers OPG, sRANKL, NF-κB , and TFF3 show promise in the diagnosis of active IBD. The decrease in NF-κB  and TFF3 following treatment suggests that be used as biomarkers to track disease activity and treatment effectiveness.