Neonatal herpes simplex virus infection (HSV) is rare in neonates, with an estimated global incidence of 10 per 100,000 live births. Neonatal HSV is challenging to diagnose due to often vague signs and symptoms. Untreated, the mortality of some HSV subtypes exceeds 80%. Overtesting and overtreatment can result in prolonged hospitalizations and expose neonates to medication toxicity. In contrast, prompt evaluation and use of empiric antiviral therapy before the results of definitive testing can improve outcomes for infants with HSV. A wide degree of practice variation exists with respect to testing and treatment for neonatal HSV, and more research is required to safely risk-stratify this population. This review presents the epidemiology, risk factors, presenting features, and emergency department management of neonatal HSV infection.