Background <p>Cronkhite–Canada Syndrome is an exceptionally rare, sporadic disorder of unknown etiology characterized by hamartomatous gastrointestinal polyps, ectodermal changes, and malabsorption. Reporting this case is crucial owing to its rarity, the associated positive autoantibodies, and the patient’s remarkable response to combined therapy, which adds valuable insight to the limited data on Cronkhite–Canada syndrome management.</p> Case presentation <p>A 59-year-old Pakistani male presented with chronic diarrhea, weight loss, nail dystrophy, and hyperpigmentation. Clinical examination, endoscopic findings, and histological analysis confirmed the diagnosis of Cronkhite–Canada syndrome, with positive autoantibodies and associated hypothyroidism. The patient was treated with prednisolone, mesalazine, and azathioprine, leading to dramatic improvements, including resolution of diarrhea and polyposis, weight gain, nail regrowth, and reduced hyperpigmentation. Laboratory parameters normalized, and the patient remained in remission off treatment.</p> Conclusion <p>This case highlights the importance of recognizing Cronkhite–Canada syndrome’s clinical, endoscopic, and histological features. The patient’s excellent response to immunosuppressive therapy underlines its potential as an effective treatment strategy, offering valuable insights into managing this rare condition.</p>