This study examines the role of infectious diseases in neonatal mortality across various African regions, with a particular focus on regional disparities in death causes. Using data from the Maternal and Child Epidemiology Estimation (MCEE) database, the analysis covers mortality rates from 2000 to 2021 across five African regions: Central, East, North, Southern, and West Africa. Prematurity, birth asphyxia, and acute lower respiratory infections were found to be the leading causes of neonatal death, with lower-income regions experiencing significantly higher mortality rates. The study highlights the effectiveness of interventions against diseases like measles and malaria, but points to the ongoing burden of preventable conditions such as sepsis and birth trauma. The findings emphasize the need for region-specific healthcare policies, particularly in low-income areas, to address gaps in maternal and neonatal care. Investments in healthcare infrastructure, infection control, and neonatal care practices are critical to reducing preventable deaths and improving neonatal outcomes across the continent.