The prevalence of gastrointestinal disorders caused by alcohol, Helicobacter pylori, non-steroidal anti-inflammatory drugs, chronic stress and sedentary lifestyle is on the rise. Calcitonin gene-related peptide (CGRP), a 37-amino acid neuropeptide, has emerged as a protective factor against various gastrointestinal issues. Despite its known benefits, the dual role of CGRP in gastrointestinal damage remains unclear. Discovered 30 years ago through alternative RNA processing of the calcitonin gene, CGRP is known to be a potent vasodilator involved in crucial defensive mechanisms for both physiological and pathological conditions. Promising evidences from preclinical research have attracted the interest of scientists for the exploration of CGRP as a therapeutic neuropeptide. Numerous evidences suggest that this neuropeptide is secreted by the neurons under the influence of endogenous as well as exogenous stimuli. CGRP repairs the gastric mucosal barrier and maintain mucosal integrity by suppressing NF-κB activation, thereby reducing tumour necrosis factor-alpha expression. In addition, recent studies suggest that CGRP modulates immune responses and enhances epithelial cell proliferation, further contributing to its cytoprotective effects. Consequently, CGRP and the CGRP secretagogues represent promising novel targets for clinical applications. This review aims to elucidate the role of CGRP and CGRP secretagogues in the management of gastrointestinal disorders, highlighting its potential as a therapeutic agent in the context of evidence-based modern gastroenterology.