Objective To study the clinical features of neonatal enterovirus infection, especially severe enterovirus infection. Methods A retrospective analysis was performed for the clinical data of 244 neonates with enterovirus infection. According to the severity of infection, they were divided into a common infection group with 231 neonates and a severe infection group with 13 neonates. Clinical features were compared between the two groups. Results Of the 244 neonates, 207 (84.8%) developed the disease in May to October, with the highest number of patients in June to July. Compared with the common infection group, the severe infection group had a significantly lower gestational age at birth and a significantly higher proportion of preterm infants (P < 0.05). Compared with the common infection group, the severe infection group had a significantly earlier onset time (P < 0.05) and significantly higher incidence rates of skin petechiae and ecchymosis, respiratory symptoms, sepsis-like manifestations (poor appetite, crying less, and less movement), concomitant diseases (such as pneumonia, myocarditis, necrotic hepatitis, and coagulation disorder), thrombocytopenia, prolonged prothrombin time, elevated creatine kinase-MB, and elevated alanine aminotransferase (P < 0.05). The severe infection group had a significantly higher mortality rate than the common infection group (P < 0.05). Conclusions There are significant differences in onset time, common clinical manifestations, and concomitant diseases between the neonates with common and severe enterovirus infection. In the enterovirus epidemic season, if the neonates have rashes and/or sepsis-like manifestations such as poor appetite and less movement, especially if the laboratory tests suggest liver damage and coagulation dysfunction, it is necessary to pay particular attention to the possibility of severe enterovirus infection.