BACKGROUND: The clinical manifestations of COVID-19 in neonates are generally mild and commonly require only supportive treatment. However, it is important to note that they can sometimes present with symptoms like bacterial sepsis, which can lead to confusion in diagnosis. In this study, our objective was to compare laboratory data and clinical manifestations between 2 groups to identify opportunities for reducing the unnecessary use of antibiotics. METHODS: The study was conducted as a cross-sectional study between January 2020 and 2023 on neonates who were admitted to the neonatal intensive care unit or the neonatal ward of Children's Medical Center in Tehran, Iran. We specifically compared the laboratory data and clinical characteristics of neonates who tested positive for either a blood culture or a reverse transcription polymerase chain reaction for COVID-19. RESULTS: Sixty-seven neonates in COVID-19 group and 68 neonates in the bacterial sepsis group entered. Prominent symptoms in the bacterial sepsis group include vomiting, seizure, apnea, mottling, increased need for ventilation and laboratory findings showing elevated levels of C-reactive protein and thrombocytopenia. In the COVID-19 group, patient exhibit symptoms such as cough, diarrhea, fever and laboratory findings that indicate neutropenia and leukopenia. Symptoms of nervous involvement were rare in this group. CONCLUSION: It is crucial to carefully assess the symptoms, laboratory results and overall condition of the patient before deciding on antibiotic initiation. By combining rapid COVID-19 testing and clinical variables, it is possible to identify low-risk infants who are unlikely to have bacterial infections.