Background <p>Pediatric sepsis remains a leading cause of morbidity and mortality in critically ill children. Early identification of reliable prognostic markers is crucial for timely intervention and improved outcomes. This study aimed to assess the value of the systemic immune-inflammatory index (SII) and the systemic inflammation response index (SIRI) in predicting mortality rate associated with sepsis in children.</p> Methods <p>This observational retrospective study gathered medical data from the electronic medical records of children diagnosed with sepsis admitted to the PICU between October 2022 and September 2023.</p> Results <p>This study included 167 pediatric patients, of whom 136 individuals (81.4%) were discharged, while 31 patients (18.6%) unfortunately did not survive. The median age of the patients was found to be 19 months. The deceased patients showed significantly higher levels of Systemic Immune-Inflammation Index (SII), and Systemic Inflammation Response Index (SIRI) compared to the group of patients who survived. In the present study, both SII and SIRI were significantly associated with mortality in univariate analysis; however, only SIRI retained independent prognostic significance after adjustment for confounding variables in the multivariate model. The ROC curve analysis indicated that SIRI and SII could predict sepsis mortality, with AUC values of 0.702 and 0.618, respectively.</p> Conclusions <p>Elevated SII and SIRI were both associated with mortality in pediatric sepsis; however, SIRI exhibited superior discriminative ability and retained independent prognostic significance, highlighting its potential utility as a clinically applicable biomarker for mortality risk stratification in this patient population.</p>