Objective To explore the correlation of eosinophil (EOS) counts and absolute monocyte count (AMC) with the severity of preterm infants with necrotizing enterocolitis (NEC). Methods A total of 209 preterm infants with NEC were retrospectively selected as the NEC group. According to the ratio of 1∶1, non⁃NEC preterm infants who were hospitalized during the same period and within 7 days of gestational age difference at birth were selected as the control group. (1) The EOS counts and AMC of preterm infants in the NEC group were collected at 3 time points as follows: within 7 days before onset (T1), at onset (T2), and within 24 hours after onset (T3); furthermore, the general clinical data and EOS counts and AMC at T1 time point were collected. (2) According to Bell staging, the NEC group was divided into stage Ⅱ subgroup (n=154) or stage Ⅲ subgroup (n=55). The clinical data, EOS counts and AMC at different time points (T1, T2 and T3) were compared between the two subgroups, and the efficacy of EOS counts and AMC at T1, T2 and T3 in distinguishing stage Ⅱ from stage Ⅲ NEC was analyzed. The LASSO regression and multivariate Logistic regression were adopted to analyze the risk factors for stage Ⅲ NEC and evaluate their predictive value. Results (1) There was no statistically significant difference in EOS counts and AMC between the NEC group and the control group at T1 time point (P>0.05). (2) stage Ⅲ subgroup exhibited higher AMC as compared with stage Ⅱ subgroup at T1 time point (P<0.05), whereas lower EOS count and AMC as compared with stage Ⅱ subgroup at T2 and T3 time points (P<0.05). Stage Ⅱ subgroup exhibited lower EOS counts at T2 time point than at T1 and T3 time points (P<0.05). However, there was no statistically significant difference in AMC between 3 time points of this subgroup (P>0.05). Stage Ⅲ subgroup interpreted lower EOS counts and AMC at T2 and T3 time points as compared with T1 time point (P<0.05). (3) At T1, T2, and T3 3 time points, areas under the curve (AUC) of EOS counts and AMC in distinguishing NEC stage Ⅱ from stage Ⅲ were 0.543, 0.649, 0.786, and 0.608, 0.678, 0.763, respectively. (4) The results of multivariate Logistic regression analysis revealed that small gestational age at birth, portal vein aeration indicated by imageology, EOS counts at T2 time point<0.07×109/L, and AMC at T2 time point<0.50×109/L were the independent risk factors for the occurrence of stage Ⅲ NEC in preterm infants (P<0.05), and their AUC for predicting stage Ⅲ NEC was 0.648, 0.684, 0.634, and 0.677, respectively, which were lower than the AUC of the combined prediction of the four indices (0.845, P<0.05), and the sensitivity and specificity of the combined prediction were 90.9% and 70.1%, respectively. Conclusions When suffering from NEC, preterm infants with stage Ⅲ NEC have a more significant decline in EOS counts and AMC and a slower recovery as compared with preterm infants with stage Ⅱ NEC. The decrease of EOS counts and AMC are related to the severity of NEC in preterm infants, which are effective indices to predict the severity of NEC. The combination of gestational age at birth and portal vein aeration can further improve the prediction efficiency.