Background and Clinical Significance: Infective endocarditis (IE) is a serious condition with rising incidence, frequently caused by Staphylococcus aureus. However, cases involving rare congenital anomalies such as Gerbode’s defect are uncommon. Case Presentation: This report presents the first documented case of IE in a patient with a congenital Gerbode defect complicated by DRESS syndrome—a severe, drug-induced hypersensitivity reaction typically triggered by antibiotics like oxacillin. A 65-year-old woman developed infective endocarditis involving vegetations on the cardiac device lead, the tricuspid valve, and adjacent to a Gerbode defect. The diagnosis was confirmed by positive blood cultures and echocardiographic findings. She received treatment with oxacillin. Subsequently, she exhibited clinical features consistent with DRESS syndrome, including rash, eosinophilia, and multi-organ involvement. Rapid recognition and management, including corticosteroid therapy and antibiotic modification, led to clinical improvement. Conclusions: This case highlights the importance of vigilance for DRESS syndrome in prolonged antibiotic therapy for IE, especially in the context of rare congenital cardiac anomalies. In addition, guidelines are needed to optimize the diagnosis and treatment of this potentially lethal complication.