Infective endocarditis (IE) is life-threatening and can lead to complications if left untreated. A 56-year-old gentleman presented with acute delirium, fever and rigor. Panton-Valentine leukocidin (PVL)-positive Staphylococcus aureus (S. aureus) was isolated in the blood culture and the PR interval was prolonged on the electrocardiogram (ECG). However, the transthoracic echocardiogram (TTE) and transoesophageal echocardiogram (TOE) at presentation were unremarkable with no evidence of intracardiac vegetations. Despite expedient intravenous antibiotics, an acquired ventricular septal defect (VSD) developed, which required urgent cardiothoracic surgical repair. It is imperative to consider early surgical interventions and the use of anti-toxin antibiotics in PVL-positive S. aureus IE.