Background: Addressing the target of sustainable development goals of reducing perinatal mortality was still a global challenge, and it is a concern in Ethiopia. Therefore, this study planned to determine the incidence and determinants of neonatal mortality in the first three days among babies delivered in Amhara Regional State’s referral hospitals. Methods: A hospital-based prospective cohort study design was conducted among 810 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; among those whose mothers labour was not monitored with a partograph, mothers experience postpartum haemorrhage, develop fistula in the first 24 hours, and experience obstructed labour. However, 39% were less risky among newborns whose mothers were directly admitted and whose mothers had visited health facilities in less than 1-hour, both. Conclusions: This study revealed that about 1 in 7 newborns died in the early three days of life. Timing of the first antenatal visit, quality of labour monitoring, maternal complications, and delay in seeking the care were the determinants. Thus, scaling-up of evidence-based interventions and harmonized efforts to improve antenatal care quality, promote institutional deliveries, provide optimal essential and emergency obstetric care, and ensure immediate postnatal care may improve neonatal survival.