Sepsis is a major cause of neonatal morbidity and mortality [
1,
2,
3]. In routine clinical practice, the rapid and accurate diagnosis of neonatal sepsis is often difficult because the clinical presentation of neonatal sepsis may be confused with non-infectious disorders, the onset of sepsis may be acute, and the clinical process can quickly subside. Improving the accuracy of diagnostic testing may improve outcomes in those with true sepsis and decrease the indiscriminate use of antibiotics in those without sepsis [
4]. Microbial cultures can help identify serious bacterial infections, but these often produce false negative results, especially after maternal use of antibiotics and may produce false positive results due to sample contamination. In addition, microbial cultures have a time delay (2–3 days) in obtaining results. Therefore, neonates with clinical manifestations of sepsis or risk factors for serious bacterial infections are usually treated with antibiotics while waiting for the results of microbiology testing [
5]. This inevitably leads to the overuse of antibiotics, which in turn may lead to the emergence of multiple drug-resistant bacteria in the neonatal intensive care unit (NICU) [
3,
6]. Therefore, to prevent microbial resistance due to unnecessary empirical treatment and to avoid unnecessary hospitalization, a definitive diagnosis should be ensured based on laboratory tests with higher diagnostic value [
7]. Biomarkers can be important in the timely diagnosis of sepsis, helping in the differential diagnosis of non-infectious diseases and decision-making in initial treatment. C-reactive protein (CRP) is produced by the liver in response to inflammation and/or infectious stimuli, and thus it is considered to be an acute-phase protein [
8,
9]. CRP may also be increased in some antenatal conditions, such as fetal distress, stress delivery, and maternal fever, in the absence of systemic infection [
8]. Therefore, its specificity is low, and it is preferably used in combination with another serum biomarker. Procalcitonin (PCT) appears to be one of the most promising among the different molecules studied as biomarkers of sepsis. PCT is a procalcitonin precursor protein produced by monocytes and hepatocytes. After exposure to bacterial endotoxin, PCT levels within 2–4 h rise sharply, within 6–8 h they reach a plateau, and then they return to normal levels after 24 h [
8,
10]. Serum PCT levels appear to correlate with the severity of the microbial attack and rapidly decrease after appropriate antibiotic treatment. In contrast to CRP, local bacterial infections, severe viral infections, and inflammatory reactions of non-infectious origin are either not associated with increased PCT or are only associated with a slight increase in PCT. In healthy and preterm neonates, there is a physiological increase in serum PCT after birth that peaks at 24 h of age [
8,
10]. Presepsin is a nicked truncated form of soluble CD14 (sCD14), which is released by detachment from the surface of immune cells after stimulation by pathogens. Recently, presepsin has been described as a reliable diagnostic and prognostic marker for neonatal sepsis. Based on the above considerations, we performed a meta-analysis to compare the diagnostic accuracy of PCT, CRP, PCT combined with CRP, and presepsin in diagnosing neonatal sepsis.