The incidence of Neonatal Systemic Inflammatory Response Syndrome (SIRS) is a critical concern in neonatal care. This study aimed to identify maternal laboratory parameters predictive of SIRS in newborns, focusing on the establishment of diagnostic cutoffs and evaluating the predictive power of these biomarkers. This prospective cohort study was conducted from January 2023 to January 2024 across several regional hospitals specializing in neonatal care. It included 207 mother-newborn pairs, divided into groups based on the neonatal development of SIRS (66 cases) or its absence (141 controls). Key maternal parameters measured included inflammatory markers and liver enzymes, analyzed using standard biochemical methods. The study applied receiver operating characteristic (ROC) analysis to establish optimal cutoff values and conducted multivariate logistic regression to determine hazard ratios (HRs) for SIRS prediction, with adjustments for potential confounders. The study identified significant ROC/AUC values for several biomarkers. The neutrophil-to-lymphocyte ratio (NLR) demonstrated an AUC of 0.926, with a cutoff value of 3.64, achieving 81.8% sensitivity and 90.9% specificity ( < 0.001). The systemic immune-inflammation index (SII) showed an AUC of 0.819 and a cutoff of 769.12, with 75.8% sensitivity and 81.8% specificity ( < 0.001). Multivariate regression analysis highlighted that neonates with maternal SII values above this cutoff were three times more likely to develop SIRS (HR 3.09, 95% CI 2.21-4.17, < 0.0001). Other notable biomarkers included dNLR and ALRI, with respective HRs of 1.88 ( = 0.018) and 1.75 ( = 0.032). These findings confirm the significant predictive value of specific maternal inflammatory markers for neonatal SIRS. These findings support the utility of these biomarkers in prenatal screening to identify neonates at increased risk of SIRS, potentially guiding preemptive clinical interventions.