Objectives Coxsackievirus B3 (CVB3) is a single-stranded RNA included in the “Human Enterovirus B” category associated with multiple, even severe, health issues in humans. Newborns are at risk of life-threatening conditions due to enteroviral infections. In newborns, the infection can be transmitted vertically, intrapartum or postpartum, and potentially through breast milk. Neonatal sepsis may result in severe complications, such as liver failure and pulmonary hemorrhage, with subsequent death. Case presentation A male newborn was admitted to the emergency department with fever, generalized hypotonia, hypo-reactivity to external stimuli, multiple episodes of apnea and desaturation, and metabolic acidosis. Laboratory studies revealed disseminated intravascular coagulation, and evidence of progressive multiorgan failure. Polymerase chain reaction performed on specimens collected at the time of admission returned positive for Enterovirus, specifically Coxsackievirus B3 VP1 gene. The patient eventually succumbed after several days due to severe sepsis, despite aggressive treatment with immunoglobulins and Pleconaril. An autopsy revealed hemorrhage in the lung, liver, heart, and gastric mucosa. Conclusions Enteroviral neonatal infections should be included in the differential diagnosis of a newborn presenting with fever, failure to thrive, and hyporeactivity, especially if symptoms arise during the classic CVB3 season. Maternal medical history should be reviewed for any possible febrile symptoms associated with a recent enterovirus infection. Aggressive treatment with immunoglobulins and, if available, Pleconaril could effectively treat the infection.