Abstract Background Sepsis is a major cause of intensive care unit (ICU) admission. Procalcitonin (PCT) could be an important prognostic marker for sepsis. Pentraxin 3 (PTX3) and PCT are detectable in patients with sepsis within a large time window after the onset of sepsis. Objective To assess the prognostic value of the PTX3, PCT in neonatal sepsis in comparison with other sepsis screen. Patients and Methods A prospective study included 40 neonates with sepsis. The study had been conducted in the neonatal intensive care units of Ain Shams University, Children’s Hospital during the period from January 2020 to May 2022. All neonates had been subjected to clinical examination, anthropometric measurements and sepsis scoring by neonatal sequential organ failure assessment (nSOFA). Laboratory investigations were collected from all pediatrics including Complete blood count (CBC), quantitative C- reactive protein (CRP), blood culture, serum pentraxin 3 (PTX3) and serum procalcitonin (PCT). Sepsis markers had been obtained from neonates at the day of being with suspected sepsis before starting the antimicrobial therapy (Day 0). While blood samples for sepsis markers reobtained only from neonates with positive blood cultures on the 3rd (Day3), accordingly our patients divided into improved and deteriorated groups. Results There was a significant decrease in CRP level and increase in procalcitonin and pentraxin 3 levels in deteriorated group than improved group at baseline with p-value = 0.004, 0.016 and 0.019; respectively. Also, the study shows that there was a significant increase in CRP, procalcitonin and pentraxin 3 levels in deteriorated group than improved group after 3 days with p-value = 0.002, <0.001 and <0.001; respectively. Furthermore, in improved group, there was a significant decrease in the level of CRP, procalcitonin and pentraxin 3 after 3 days than at baseline with p-value = 0.001, <0.001 and 0.001; respectively. Also in deteriorated group, there was statistically significant increase in the CRP and pentraxin 3 levels after 3 days than at baseline in deteriorated group with p- value = 0.002 and 0.019; respectively while no change found in procalcitonin level. Conclusion Serum pentraxin 3 and procalcitonin levels seem to be promising prognostic markers in neonatal sepsis with higher sensitivity and specificity for procalcitonin than pentraxin at 3 days.