Infective endocarditis is an infection of the inner layers of the heart, seen often in intravenous drug users and patients with valvular lesions or prosthetic heart valves. This entity has high mortality and morbidity. The most common causative microorganism isStaphylococcus aureus. In this comprehensive literature review, we focused on bothStaphylococcus aureusinfections, i.e., methicillin-sensitiveStaphylococcus aureus(MSSA) and methicillin-resistantStaphylococcus aureus(MRSA) endocarditis, demographics, use of transthoracic echocardiogram and/or transesophageal echocardiogram for diagnostics, and treatments. Although clinical criteria are relevant, transesophageal echocardiogram plays a vital role in establishing and identifying the presence of infective endocarditis and its local complications, with higher sensitivity in patients with prosthetic valves. The antibiotic selection posed a great challenge for clinicians due to antibiotic resistance and the aggressive nature ofStaphylococcus aureus. Early diagnosis of infective endocarditis, when suspected, and effective management by a multispecialty team can improve the outcome for the patients.