Background: The first 28 days of life- the neonatal period is the most vulnerable time for a child’s survival. Globally, neonatal mortality has seen a downward trend in recent years. The main objective of this study was to determine the percentage of neonatal mortality and to provide information on factors associated with neonatal mortality at the neonatal unit of a tertiary health facility or teaching hospital. Methods: Data of neonates admitted to the neonatal in-patient unit of the Komfo Anokye Teaching Hospital (KATH) in Ghana from January 2013 to May 2014 were analyzed. Logistic regression model was performed to assess the association between neonatal mortality and predictors. Results: A total of 5,195 neonatal admissions were recorded. The overall percentage of neonatal mortality was 20.2%. Infants with very low birth weight, having 5-minute Apgar score lower than 4, newborns with pre-term delivery, being referred from other health facilities, and being diagnosed with respiratory distress and birth asphyxia had a higher percentage of neonatal mortality. Conclusion: The mortality at the neonatal in-patient unit at the Komfo Anokye Teaching Hospital in Ghana is very high. There is the need for continuous attention and interventions to help reduce the risk of mortality among neonates admitted to the facility.