Gastrointestinal Tuberculosis (GITB) and Crohn’s disease (CD) are both chronic granulomatous diseases with a predilection to involve primarily the terminal ileum. GITB is often considered a disease of the developing world, while CD and inflammatory bowel disease are considered a disease of the developed world. But in recent times, the epidemiology of both diseases has changed. Differentiating GITB from CD is of immense clinical importance as the management of both diseases differs. While GITB needs anti-tubercular therapy (ATT), CD needs immunosuppressive therapy. Misdiagnosis or a delay in diagnosis can lead to catastrophic consequences. Most of the clinical features, endoscopic findings, and imaging features are not pathognomonic for either of these two conditions. The definitive diagnosis of GITB can be clinched only in a fraction of cases with microbiological positivity (acid-fast bacilli, mycobacterial culture, or PCR-based tests). In most cases, the diagnosis is often based on consistent clinical, endoscopic, imaging, and histological findings. Similarly, no single finding can conclusively diagnose CD. Multiparametric-based predictive models incorporating clinical, endoscopy findings, histology, radiology, and serology have been used to differentiate GITB from CD with varied results. However, it is limited by the lack of validation studies for most such models. Many patients, especially in TB endemic regions, are initiated on a trial of ATT to see for an objective response to therapy. Early mucosal response assessed at two months is an objective marker of response to ATT. Prolonged ATT in CD is recognized to have a fibrotic effect. Therefore, early discrimination may be vital in preventing the delay in the diagnosis of CD and avoiding a complicated course.