Objective: To investigate the relationship between serum, 6-phosphate glucose dehydrogenase (G6PD), high-sensitivity C-reactive protein (hs CRP), amyloid A (SAA), procalcitonin (PCT) levels and prognosis in neonatal sepsis (NS). Method: 118 NS patients admitted to the neonatal intensive care department of XXX Hospital from January 2022 to June 2024 were selected, and 59 healthy newborns from the same period were selected as the control group. Compare the serum levels of G6PD, hs CRP, SAA, and PCT between the NS group and the control group; According to the prognosis after one month of treatment, NS patients were divided into a good prognosis group and a poor prognosis group. The general information and serum G6PD, hs CRP, SAA, and PCT levels of NS patients with different prognoses were compared; Logistic regression analysis and receiver operating characteristic curve (ROC) were used to analyze the prognostic factors of NS patients and the predictive value of serum G6PD, hs CRP, SAA, and PCT for prognosis. Compared with the control group, the NS group showed a decrease in serum G6PD levels and an increase in hs CRP, SAA, and PCT levels (P<0.05); According to the prognosis after one month of treatment, there were 86 cases in the good prognosis group and 32 cases in the poor prognosis group. The serum G6PD level in the poor prognosis group was lower than that in the good prognosis group, and the hs CRP, SAA, and PCT levels were higher than those in the good prognosis group (P<0.05); Logistic regression analysis showed that elevated levels of serum hs CRP and SAA were associated with poor clinical prognosis (P<0.05); The area under the curve (AUC) for predicting poor prognosis using serum G6PD, hs CRP, SAA, and PCT levels was 0.804, 0.876, 0.868, and 0.720, with sensitivities of 62.50%, 71.87%, 75.00%, and 65.62%. The AUC for predicting poor prognosis in NS patients using a combination of serum G6PD, hs CRP, SAA, and PCT was 0.903, with a sensitivity of 78.12% (P<0.05). Conclusion: The serum G6PD level in NS patients is reduced, while the serum hs CRP, SAA, and PCT levels are increased. The combined detection of serum G6PD, hs CRP, SAA, and PCT has the best predictive power for poor prognosis.