Pembrolizumab is a promising checkpoint inhibitor for advanced urothelial carcinoma. Like other immunotherapies, it can cause rare immune-related adverse events. The spontaneous rupture of the urinary bladder after the intravenous injection of pembrolizumab is rare and has not been reported. Here, we present a 74-year-old man patient case of locally advanced transitional cell carcinoma of the urinary bladder who presented severe abdominal pain the same day of the second dose of pembrolizumab administration. The exploratory laparotomy revealed intraperitoneal rupture of the urinary bladder associated with peritonitis. After surgical repair, the patient's condition improved. The purpose of this report is to discuss the possible association of bladder perforation in bladder cancer with pembrolizumab immunotherapy, its management, and the importance of early recognition to prevent more fatal complications.