Background: Necrotizing enterocolitis (NEC) is the most common acquired multifactorial gastrointestinal emergency that primarily affects pre-term infants. It's a fatal condition, especially in low-birth-weight neonates. Objective: To assess the value of fecal calprotectin as an early non-invasive indicator for the diagnosis of NEC. Patients and Methods: This is a case-control cross-sectional study that included 50 neonates admitted to the NICU in Aswan Specialized Hospital who suffered from NEC, compared to 50 completely healthy neonates as a control group born between May 2021 and October 2022. All infants enrolled in this study were subjected to through history taking, complete clinical examination, and laboratory investigations including; (CBC, CRP. ABG, serum sodium level fecal calprotectin), and radiological imaging (plain erect abdominal x-ray and abdominal US). A small amount of stool (0.5gm) was needed to detect calprotectin concentration in the fecal sample using ELISA. Results: We found that there was a significant correlation between the disease WBCs and CRP. Moreover, fecal calprotectin showed a significant difference between diseased cases and control. Also, there was no correlation between fecal calprotectin and post-natal age, gestational age, or sex. However, there's a strong significant positive correlation between fecal calprotectin and CRP in all the diseased cases. Fecal calprotectin among the control group was 20 (17-29.25) mg/gm stool and among the case group was 198.5 (186- 240.75).mg/gm stool Conclusion: We concluded that fecal calprotectin can be used as a very useful diagnostic biomarker for NEC especially in the early stage of the disease in both preterm and full-term where the clinical, laboratory, and radiological investigations could be non-specific