Background Hyaline membrane disease (HMD) is a leading cause of morbidity and mortality in preterm newborn babies. Though, there are studies related to Hyaline membrane disease inclusive of all neonates, studies related to the burden among preterm neonates were limited. In addition, increasing neonatal mortality in Ethiopia could be related to increase in the burden of hyaline membrane disease among preterm neonates. Therefore, this study was aimed to assess the burden of hyaline membrane disease, mortality and its associated factors among preterm neonate admitted at neonatal intensive care unit, North Central Ethiopia. Methodology An institution-based retrospective follow-up study was conducted among 535 preterm neonates admitted at neonatal intensive care unit from January 1, 2014-December 30, 2017. Data were entered into EPi-data 220.127.116.11 and transferred to STATA version 14 statistical software for statistical analysis. Binary logistic regression was used for the analysis. All variables with P-value Results In the current study, proportion of hyaline membrane disease was 40% (95% CI; 35.8, 44.3) of which 49.5% died. Preterm neonate born with Gestational age of less than 34 weeks of age (Adjusted odd ratio (AOR = 2.64; 95 CI: 1.49, 4.66)), 5.sup.th minute Apgar score less than 7 (AOR = 2.2; 95% CI: 1.20, 4.07), and newborn with birth weight of less than 1500 gram (AOR = 2.4, 95% CI: 1.3, 4.3) were predictors of hyaline membrane disease. Conclusions The mean gestational age (±) was 33.46 (±2.55) weeks. The incidence of hyaline membrane disease among preterm admissions was high. Preterm neonate born with gestational age of less than 34 weeks of age, asphyxiated newborns and newborn with birth weight of less than 1500 gram were predictors of hyaline membrane disease. So, emphasis should be given on early screening, follow up and timely interventions for preterm neonate.