Objectives: Essential newborn care is a set of comprehensive recommendations designed by the World Health Organization to improve the newborn’s health through intervention before conception, during pregnancy, soon after birth, and the postnatal period. Globally 4 million newborns die every year before they reach the age of 1 month. Therefore, this study assessed the level of knowledge and associated factors toward essential newborn care practices among postnatal mothers attending postnatal service in governmental hospital of Harar town, Eastern Ethiopia, 2020 Methods: Facility-based cross-sectional study was conducted in Harar Town, Jugul, and HiwotFana Specialized University Hospital. Voluntary postnatal mothers who are randomly selected were participated in the study. A total number of 266 women were included in the study. Data were collected through face-to-face interviews. The training was given for data collectors, and data evaluation was done on daily basis. Cleaned data were entered to SPSS version 20, and multiple logistic regression analysis was used for better prediction of determinants and to reduce bias due to confounders. Those variables with a p value less than 0.25 were entered into multiple logistic regression analyses. Associations with p value less than 0.05 were declared as statistically significant. Text, figures, and tables presented the result. Result: The overall prevalence of good knowledge was 57.2%. Educational status, average monthly income, antenatal care visit, and parity had significantly associated with outcome variables. Conclusion: More than half of mothers had inadequate newborn care knowledge. In addition, educational status, average family monthly income, frequency of antenatal care visit, and parity were independently associated with knowledge on essential newborn care. Therefore, more significant improvement in essential newborn care practices could be attained through policy implications and recommendations. Therefore, we recommend that stakeholders of the health sector have a close follow-up on maternal and newborn care services and maintain a strategy that will incorporate maternal education service on essential newborn care practice.