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Background: Neonatal mortality remains a serious global public health problem, but Sub-Saharan Africa (SSA), in particular, is largely affected. Current evidence on neonatal mortality is essential to inform programs and policies, yet there is a scarcity of information concerning neonatal mortality in our study area. Therefore, we conducted this prospective cohort study to determine the incidence and predictors of neonatal mortality at Debre Markos Referral Hospital, Northwest Ethiopia., Methods: This institutionally-based prospective cohort study was undertaken among 513 neonates admitted to the neonatal intensive care unit of Debre Markos Referral Hospital between December 1st, 2017 and May 30th, 2018. All newborns consecutively admitted to the neonatal intensive care unit during the study period were included. An interviewer administered a questionnaire with the respective mothers. Data were entered using Epi-data™ Version 3.1 and analyzed using STATA™ Version 14. The neonatal survival time was estimated using the Kaplan-Meier survival curve, and the survival time between different categorical variables were compared using the log rank test. Both bi-variable and multivariable Cox-proportional hazard regression models were fitted to identify independent predictors of neonatal mortality., Results: Among a cohort of 513 neonates at Debre Markos Referral Hospital, 109 (21.3%) died during the follow-up time. The overall neonatal mortality rate was 25.8 deaths per 1, 000 neonate-days (95% CI: 21.4, 31.1). In this study, most (83.5%) of the neonatal deaths occurred in the early phase of neonatal period (< 7 days post-partum). Using the multivariable Cox-regression analysis, being unemployed (AHR: 1.6, 95% CI: 1.01, 2.6), not attending ANC (AHR: 1.9, 95% CI: 1.01, 3.5), not initiating exclusive breastfeeding (AHR: 1.7, 95% CI: 1.02, 2.7), neonatal admission due to respiratory distress syndrome (AHR: 2.0, 95% CI: 1.3, 3.1), and first minute Apgar score classification of severe (AHR: 2.1, 95% CI: 1.1, 3.9) significantly increased the risk of neonatal mortality., Conclusion: In this study, we found a high rate of early neonatal mortality. Factors significantly linked with increased risk of neonatal mortality included: unemployed mothers, not attending ANC, not initiating exclusive breastfeeding, neonates admitted due to respiratory distress syndrome, and first minute Apgar score classified as severe.