Background: Addressing, the target of sustainable development goals of reducing perinatal mortality, was still a global challenge, and the magnitude of newborn death in the first three days of life takes a significant role in Ethiopia. Therefore, this study planned to determine the incidence and determinants of neonatal mortality in the first three days among babies delivered in referral hospitals of Amhara Regional State, North-Western Ethiopia. Method: A hospital-based prospective cohort study design was conducted among 810 early neonates in the first three days of delivery between March 1 and August 30, 2018. The neonates were followed, starting from the time of admission to 72 hours. An interviewer-administered questionnaire and medical record review were conducted for data collection. Data were entered into Epi-data manager version 4.4 and analyzed using STATA™ version 16.0 for the analysis. Cox-Proportional hazard model was used to determine the survival time of the newborns. Results: The overall incidence of newborn mortality in this study was 151/1,000 births. Neonatal mortality was significantly high among newborns whose mothers came between 17 and 28 weeks of gestation for the first visit [AHR=1.67;95% CI: 1.02, 2.73], among those whose mothers labor was not monitored with a partograph [AHR=2.66; 95% CI: 1.70, 4.15], mothers experience postpartum hemorrhage [AHR 2.88; 95% CI: 1.69, 4.89], develop fistula in the first 24 hours [AHR=3.75; 95% CI: 1.23, 11.43], and experience obstructed labor [AHR=2.14; 95% CI: 1.35, 3.38]. However, it was 39% less risky among newborns whose mothers were directly admitted, and whose mothers had visited health facilities in less than 1-hour, both [AHR=0.61; 95% CI: 0.38, 0.97]. Conclusion: This study revealed that about 1 in 7 newborns died in the early three days of life. The timing of the first antenatal visit, quality of labor monitoring, maternal complications, and delay in seeking the care were found to be the determinants. Thus, scaling-up of evidence-based interventions, and harmonized efforts aimed to improve the quality of antenatal care, promote institutional deliveries, provide optimal essential and emergency obstetric care, and ensure immediate postnatal care may improve neonatal survival.