BACKGROUND: Neonatal sepsis is a major global health problem with high morbidity and mortality. Despite ongoing advances in maternal and neonatal care, due to antibiotic resistance, culture-negative cases, and non-specific symptoms, the accurate diagnosis of neonatal sepsis remains challenging. METHODS: In this diagnostic test accuracy study conducted from April 2020 to September 2022, we investigated the diagnostic values of complete blood count parameters and C-reactive protein for neonatal sepsis among 277 newborns admitted to 17 Shahrivar hospital. Some characteristics (including gender and age of neonates, age of mothers, gestational age, neonatal weight, birth weight, Apgar score and the mode of delivery) were considered for the study as possible risk factors of neonatal sepsis. Also, we reviewed related studies from different countries and compared their results with the current study for a more comprehensive conclusion. All analyses were performed using SPSS software and statistical significance was defined as P<0.05. RESULTS: Our study revealed that RDW was significantly higher in probable (16.59±1.92) and proven septic groups (16.43±1.67) than non-septic group (13.37±1.19) (P=0.001). Among other CBC parameters, lower WBC value in proven sepsis group was borderline significant (P=0.05), while ANC and platelet count showed no statistically significant difference among cases and controls (P=0.273 and P=0.467, respectively). In addition, positive qualitative plasma CRP had significant relationship with the diagnosis of neonatal sepsis (P<0.001). Among considered demographic characteristics of the neonates, significant intergroup differences were detected regarding neonatal age (P<0.001), gestational age (P=0.008) and mean quantitative maternal age (P=0.037) for neonatal sepsis. At an optimal cutoff level of 14.1%, RDW had a sensitivity of 91.98% and a specificity of 82.22% for identifying neonates with probable and proven sepsis in this study. CONCLUSIONS: Available and cost-effective biomarkers, such as elevated RDW level (as the most efficient CBC parameter) and positive CRP can play an important role in the timely diagnosis of neonatal sepsis.