Fluorouracil (5-FU) belongs to a group of chemotherapy drugs known as antimetabolites. It is used to treat several types of cancer including breast cancer, head and neck cancers, and colorectal cancer. Common side effects of 5-FU include gastrointestinal problems, neutropenia, and thrombocytopenia; a few cases of 5-FUrelated hyperammonemia have also been reported. Hyperammonemia is a rare central nervous system toxicity causing loss of sense of direction, mental confusion, restlessness, hearing impairment, epilepsy, coma, or even death. While its mechanism is still unclear, factors such as renal dysfunction, constipation, weight loss, and infection are known to increase the risk of hyperammonemia. This case report was a breast cancer patient administered a high dose of 5-FU via continuous venous infusion and experienced vomiting, unconsciousness, and an abnormal increase in blood ammonia. The 5-FU administration was immediately withdrawn and oral lactulose and supplemental intravenous infusion was given. The blood ammonia returned to normal and the brain symptoms disappeared. The physician revised the patient’s cancer treatment protocol, changing the chemotherapeutic combination. In this article, the risk factors and possibilities of high-dose 5-FU continuous intravenous infusion the literature were reviewed. Physicians, pharmacists, and nursing staff should pay attention to patient status and assess risk factors during 5-FU treatment to ensure their safety.