Background. Neonatal mortality continues to be a public health problem, especially in sub-Saharan Africa. This study was conducted to assess the maternal, neonatal, and health system related factors that influence neonatal deaths in the Ashanti Region, Ghana. Methods. 222 mothers and their babies who were within the first 28 days of life on admission at Mother and Baby unit (MBU) at the Komfo Anokye Teaching Hospital (KATH) in Kumasi, Ashanti Region of Ghana, were recruited through systematic random sampling. Data was collected by face to face interviewing using open and closed ended questions. A logistic regression analysis was conducted to determine the influence of proximal and facility related factors on the odds of neonatal death. Results. Out of the 222 mothers, there were 115 (51.8%) whose babies did not survive. Majority, 53.9%, of babies died within 1-4 days, 31.3% within 5-14 days, and 14.8% within 15-28 days. The cause of death included asphyxia, low birth weight, congenital anomalies, infections, and respiratory distress syndrome. Neonatal deaths were influenced by proximal factors (parity, duration of pregnancy, and disease of the mother such as HIV/AIDS), neonatal factors (birth weight, gestational period, sex of baby, and Apgar score), and health related factors (health staff attitude, supervision of delivery, and hours spent at labour ward). Conclusion. This study shows a high level of neonatal deaths in the Ashanti Region of Ghana. This finding suggests the need for health education programmes to improve on awareness of the dangers that can militate against neonatal survival as well as strengthening the health system to support mothers and their babies through pregnancy and delivery and postpartum to help improve child survival.