Non-steroidal anti-inflammatory drugs (NSAIDs), widely used for their therapeutic benefits, are associated with significant gastrointestinal complications, including the rare occurrence of colonic diaphragm disease (CDD). Characterized by diaphragm-like fibrotic strictures that narrow the intestinal lumen, CDD often leads to symptoms such as chronic anemia, bowel obstruction, and gastrointestinal bleeding. This report discusses a case of NSAID-induced CDD in a 58-year-old male with a history of prolonged NSAID use for osteoarthritis. The patient's clinical course was marked by progressive fatigue, melena, and intestinal obstruction, necessitating multiple hospitalizations and interventions. Our findings underscore the frequent association of CDD with prolonged NSAID use, particularly enteric-coated formulations, and the predominance of lesions in the right colon. Furthermore, we conducted a comprehensive review of the literature, summarizing 53 reported cases of NSAID-induced colonic diaphragm disease. This review highlights the common clinical manifestations, diagnostic challenges, and therapeutic strategies for this rare condition. Despite medical management and endoscopic interventions, the patient required subtotal colectomy due to recurrent strictures and complications. This case underscores the diagnostic challenges posed by CDD, particularly its overlap with inflammatory bowel disease. Surgical exploration and histological evaluation were essential for diagnosing CDD and guiding appropriate management. This case highlights the importance of recognizing NSAID-induced enteropathy in the differential diagnosis of patients with unexplained gastrointestinal symptoms, emphasizing the need for a thorough drug history and tailored therapeutic strategies. Advanced surgical techniques and novel treatments continue to improve the management of gastrointestinal complications, bettering patient outcomes, and quality of life.