As specific clinical manifestations and detection tools for early neonatal infections are lacking, early detection and treatment are ongoing challenges. The present study aimed to investigate the role and clinical significance of the CD64 index in comparison with conventional examination indices (WBC, PCT and CRP) for the early diagnosis of neonatal infection. Of 74 in-patient newborns, non-sepsis (non-specific infection but free of sepsis), sepsis and control [newborns with ABO hemolytic disease of the newborn (ABOHDN) but without infection] groups involved 32, 16 and 26 cases, respectively. Peripheral blood WBC, PCT, CRP and CD64 indices were acquired for all groups. The sepsis group showed significantly higher WBC, PCT and CRP levels than the control group. Compared with the non-sepsis group, the sepsis group demonstrated significant increases in PCT but not in WBC or CRP. Compared with the control group, the non-sepsis and sepsis groups had higher CD64 indices. Combined, compared with the WBC, PCT and CRP indices, the CD64 index is unique in its capacity to diagnose neonatal infections early. The CD64 index combined with other conventional indices may lay a basis for the future early diagnosis and effective treatment of neonatal infections.