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Neonatal herpes simplex virus (NHSV) infection, although rare, is related to high rates of morbidity and mortality, both can be reduced by prompt acyclovir treatment. In contrast, enterovirus is a common cause of neonatal meningitis, with relatively negligible incidence of serious illness or long‐term sequelae, and its clinical course is not affected by acyclovir treatment. Acyclovir is associated predominantly with renal adverse effects, and its widespread application in the context of neonatal fever is not always justified. To further characterized the Israeli NHSV infection epidemiology and to evaluate the distinct clinical characteristics of NHSV and neonatal enteroviral meningitis (NEM), Israeli NHSV patients, hospitalized between January 2015 and April 2022 in 22 medical centers were assessed, together with NEM patients, hospitalized at Sheba Medical Center during the same period. NHSV demographic and clinical characteristics were documented and compared to those of NEM. Eighty‐five NHSV (73% males) and 130 NEM (62% males) patients were included. The incidence of NHSV was 5.9/100 000 live births, the common phenotype and HSV type were SEM (53%) and HSV1 (91%), respectively. Horizontal transmission was suspected in 50% cases (of which 67% underwent a Jewish ritual circumcision with direct wound sucking, 33% had relatives with highly suspicious herpetic lesions). Compared with NEM, NHSV tends to present with rash (14% vs. 60%, p < 0.01) and seizures (0% vs. 6%, p = 0.02), while fever, irritability and poor feeding appear more frequently in NEM (94% vs. 18%, p < 0.01; 37% vs. 1%, p < 0.01; 25% vs. 1%, p < 0.01, respectively). Of NEM patients, 28% were treated with acyclovir. Our results mark a decrease in the incidence rate of NHSV in Israel and a prominent mode of horizontal infection acquisition. We underscore the unique localized phenotype of NHSV, in contrast to enterovirus, which tends to cause a systemic disease with constitutional symptoms. These findings should be considered when evaluating the need for comprehensive empirical treatment for HSV in the context of neonatal fever, or according to a certain clinical presentation. [ABSTRACT FROM AUTHOR]