Background Neonatal mortality is a public health issue in, Ethiopia. Unfortunately, the issue is noticeably under-reported and underestimated, so the true gravity of the situation cannot be acknowledged in developing regions of the country. Regrettably, there is no single study to show the rates and predictors of neonatal mortality for Afar region. Thus, this study aims to assess neonatal mortality and associated factors in Afar region, Ethiopia. Methods A health facility-based cross-sectional study was conducted on 403 neonates admitted to the neonatal intensive care units (NICUs) from January 2015 to December 2019. Maternal and neonatal medical records were reviewed and audited using structured data extraction checklist. The data was collected by four trained nurses and midwives. The medical records were selected using a systematic random sampling technique. Bivariate and multivariable logistic regression analyses were done. Adjusted odds ratio with the corresponding 95% confidence interval were used to assess the association between neonatal mortality and the associated factors. Finally, the statistical significance level was declared at a p-value of less than 0.05. Results In this study, 391 medical records of newborns were included with the data complete rate of 97.02%. The prevalence of neonatal mortality was 57 (14.6%) [95% CI 11.0%-18.4%]. A multivariable logistic regression showed that lack of antenatal care (ANC) follow up [AOR = 4.69: 95%CI (1.77, 12.47)], giving birth through cesarean section [AOR 3.59, 95%CI (1.22, 10.55)], having admission temperature less than 36.5°C [AOR 10.75, 95%CI (3.75, 30.80)], birth asphyxia [AOR 7.16, 95%CI (2.22, 23.10)], and having a length of stay greater than five days in the hospital [AOR 0.23, 95%CI (0.08, 0.66)] were significantly associated with neonatal mortality. Conclusion This study revealed that the rate of neonatal mortality is still high compared to the national data. Antenatal care, cesarean section delivery, length of stay in the hospital, low temperature at admission and birth asphyxia were factors associated with neonatal mortality. Thus, the health facilities should give due attention to improve antenatal care, intrapartum care and standardized care for admitted neonates. Furthermore, prospective studies are recommended.