Objective To explore the diagnostic value of cord blood C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) for early-onset neonatal sepsis (EOS).Methods One hundred and sixty-eight neonates born in the Department of Obstetrics and transferred to the Department of Neonatology of the First Affiliated Hospital of Gannan Medical University within 3 days after birth between March 2019 and December 2019 were selected. We divided them into the EOS group (31 cases) and the control group (137 cases) according to their conditions. The cord blood CRP, PCT, and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA), and the differences in these indicators between the two groups were compared. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic efficacy of CRP, PCT, IL-6, and their combined detection for EOS.Results There was no difference in the sex ratio, gestational age or birth weight between the two groups (P > 0.05). The proportions of maternal chorioamnionitis and premature rupture of membrane were higher in the EOS group than those in the control group (P < 0.05), while the way of delivery was similar between the two groups (P > 0.05). The levels of cord blood CRP, PCT, and IL-6 in the EOS group were higher than those in the control group (P < 0.05). The areas under the ROC (AUC) curve of cord blood CRP, PCT, and IL-6 were all greater than 0.7, exhibiting high diagnostic values. However, the sensitivity ( > 80%) and specificity ( > 90%) of PCT and IL-6 but not CRP were relatively high. Compared with these indicators used alone, the combined detection of CRP, PCT and IL-6 slightly improved the AUC and specificity for diagnosing ESO, whereas the sensitivity was not as high as that of PCT and IL-6.Conclusions Cord blood CRP, PCT, and IL-6 all exhibit high diagnostic values for EOS. Choosing the most suitable indicator helps in early diagnosis of EOS, but the combined detection of the three indicators is of little significance.