Infective endocarditis (IE) is an infectious disease caused by microorganisms including bacteria and fungi that invade the endocardium and heart valves. Its neurological complications are clinically rare and associated with high mortality. Failure to recognize this condition timely will easily lead to misdiagnosis and inappropriate management, which severely impairs patient prognosis. This article reports a 76-year-old male case, whose initial presenting symptoms were fever, abnormal mental behavior and multiple lobar cerebral hemorrhages. The initial diagnosis was intracranial infection combined with sepsis. After anti-infective therapy and symptomatic conservative treatment, the patient's condition improved and he was discharged. 12 days later, the patient was re-admitted with chills and high fever. Staphylococcus aureus was isolated from two independent blood cultures, and echocardiography revealed active vegetations on the aortic valve. Combined with the modified Duke Criteria, the patient was definitively diagnosed with IE, complicated by acute heart failure, myocardial injury and severe stenosis of multiple coronary arteries. After comprehensive interventions including potent combined anti-infective therapy and cardiac function support, the patient eventually died of circulatory failure despite unsuccessful resuscitation. This case reminds clinicians that for elderly patients presenting with unexplained fever, lobar cerebral hemorrhage, and altered mental status, blood cultures should be completed as early as possible, and serial echocardiographic re-evaluation (transesophageal echocardiography when necessary) should be performed dynamically. Clinicians should adhere to a full-course standardized antimicrobial regimen, maintain high vigilance against IE with neurological injury as the initial manifestation, so as to reduce missed diagnoses and avoid delayed treatment.

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