Differentiating inflammatory bowel disease from other gastrointestinal inflammatory conditions is essential for precise diagnosis and management. Here we reviewed various infectious, ischemic, drug-induced, and rare pathologies that can mimic IBD both clinically and histologically. Intestinal tuberculosis, in particular, poses a diagnostic challenge due to its similarities to Crohn’s disease in the ileocecal region. Infectious causes, such as Yersinia or CMV, and drug-induced enteropathies, especially from NSAIDs, can produce IBD-like symptoms and morphologies. Advanced diagnostic approaches, including tissue PCR, specific histological staining, and imaging, are recommended to identify unique features, such as granulomas in ITB or vasculitic involvement in systemic vasculitis. Monogenic diseases, Behçet’s disease, and GI vasculitis also require consideration, particularly in cases resistant to standard treatments. Differentiating factors, such as symptom duration, endoscopic findings, and associated systemic signs, guide targeted diagnosis. Accurate assessment and a multidisciplinary approach enhance clinical outcomes, ensuring appropriate treatment for conditions that resemble IBD but have distinct therapeutic needs.