Background: The neonatal period is the most susceptible phase of life. In Ethiopia changes in neonatal mortality are not as significant as changes in post-neonatal and child mortality. The aim of this study was to assess the causes and factors associated with neonatal mortality at Jimma Medical Center. Materials and methods: A cross-sectional study was conducted for 11 days from February 12, 2018 at the Neonatal ICU of Jimma Medical Center. Data were extracted from the medical records of neonates admitted during a three year period from September 07, 2014 to August 31, 2017, using pretested checklists. Bivariate and multivariate logistic regressions were used to determine factors associated with neonatal mortality and P-values <0.05 were considered statistically significant. Results: Of 3,276 neonates admitted during the study period, 412 (13.3%) died, equating to a rate of 30 deaths per 1,000 institutional live births. The majority (249, 60.4%) of deceased neonates had low birth weight, while 230 (55.8%) were premature and 169(41%) had Respiratory Distress Syndrome (RDS). Residency being outside Jimma city (AOR 1.89, 95% CI: 1.43, 2.51) and the length of stay <7Days (AOR 3.93, 95% CI: 2.82, 5.50), low birth weight (AOR 1.54, 95% CI: 1.06, 2.25), prematurity (AOR 2.2, 95% CI: 1.41, 3.42), RDS (AOR 4.15, 95% CI: 2.9, 5.66), perinatal asphyxia (AOR 4.95, 95% CI: 3.6, 7.34), and congenital malformations (AOR 4, 95% CI: 2.55, 2.68) were significantly associated with neonatal mortality. Conclusions: A significant proportion of neonates attending the neonatal ICU died. Parental residency, the length of stay, low birth weight, prematurity, RDS, perinatal asphyxia, and congenital malformations were factors associated with neonatal mortality, which could be avoidable. Therefore, preventive measures such as enhancing the utilization of antenatal care services and, early identification and referral of high risk pregnancy and neonates could reduce the neonatal deaths.