Abstract Background Although all newborns are at an increased risk of developing sepsis, this is particularly true for premature infants because of their immune systems haven’t fully matured. Early detection of sepsis, prior to overt clinical deterioration, would allow earlier institution of antibiotics and supportive therapies will result in better outcomes. Aim of the Work The aim of this study was to determine the effectiveness of combination of HeRO score and NEW system in early detection of neonatal sepsis in preterm infants by using HeRO score and NEW chart combined together. Methods The study included 170 preterm infants at Ain Shams Children Hospital, Cairo, Egypt: Prospective observational study. All studied neonates were subjected to NEW and HeRO scores which displayed a number or score, which represented the risk that a patient would experience clinical deterioration. Confirmation of neonatal sepsis done by withdrawal of C-reactive protein (CRP) and Blood culture. NEW system and HeRO scores followed throughout their hospital stay. The NEW system score chart divided into 3 colours (white, Amber and red). These colours used for identifying the risk for the patient. A HeRO score of 1 is “normal” for healthy preterm infants, and a score of 5 indicates a five-fold increased risk that the patient will be diagnosed with sepsis within the next 24 hours up to 5 days. Results The total number of our studied neonates were divided according to the sepsis or not into 80 neonates were sepsis free, 69 neonates who had initial sepsis and 21 who developed sepsis and NEW and HeRO scores showed statistically higher significance in patients with initial sepsis and developed sepsis than non-septic patients. NEW and HeRO score were significantly higher in septic patients than non- septic patients as cut of value of NEW and HeRO scores was >1 and >0 respectively. Conclusion The combination of HeRO score and NEW system can be used for early detection of neonatal sepsis in preterm infants.