We report an unusual case of severe chest pain caused by N-acetylcysteine-induced esophagitis. An 81-year-old Chinese man with a history of interstitial lung disease was admitted to our hospital with intermittent arrhythmia that began 5 days ago. The patient presented with complaints of cough, sputum, and shortness of breath. Cefminox injections and N-acetylcysteine tablets were prescribed to improve respiratory symptoms. The patient developed severe chest pain and odynophagia 4 hours after swallowing the N-acetylcysteine tablet while in the decubitus position. Upper gastrointestinal endoscopy revealed four discrete areas of ulcerations measuring approximately 1 cm at the midesophageal level. The distance between the foci and the incisors was approximately 24 cm. The patient continued the N-acetylcysteine orally, which was administered in powdered form with more water while in the upright position. Pantoprazole and hydrotalcite were also administered to the patient. The symptoms subsided, and a follow-up endoscopy after 20 days showed that the ulcers healed. This case highlights that seemingly safe drugs such as N-acetylcysteine can lead to severe chest pain if ingested inappropriately.