Neonates with disseminated neonatal herpes simplex virus infection often present with cardiorespiratory failure. The pathophysiological contributors to the disease phenotype, biologic mechanisms underlying the hemodynamic instability and optimal approach to cardiovascular treatment have not been well described. We describe clinical and echocardiography features of cardiovascular dysfunction, in a case series of neonates with disseminated herpes simplex virus, and response to physiology-based hemodynamic management. The biologic phenotype includes low systemic vascular resistance state, hypovolemia secondary to third space losses, myocardial dysfunction and pulmonary hypertension. Early targeted neonatal echocardiography provided hemodynamic insights on blood flow, shunt characterization, vascular resistance and cardiac function, that were difficult to gauge clinically (eg, differentiating parenchymal from pulmonary vascular disease) thereby positively impacted clinical care. All patients were stabilized hemodynamically without utilizing extracorporeal membrane oxygenation, although all patients died of multiorgan failure.