BACKGROUND Around the world, more than three million newborns die in their first months of life every year. In Ethiopia during the last five years period; neonatal mortality is 37 deaths per 1000 live births. Even though there is an improvement compared to the past five years, there is still high home delivery 90 %, and high neonatal mortality about the Millennium Development Goal, which aims to be less than 32/1000 live births in Ethiopia. The purpose of this study is to assess maternal knowledge, practice and associated factors of essential newborn care at home in Gulomekada District Eastern Tigray, Ethiopia. METHODS A community-based cross-sectional study is conducted in 296 mothers from Gulomekada District by using simple random sampling technique. Data entry and analysis is carried out by using Statistical Package for Social Sciences-20. The magnitude of the association between different variables about the outcome variable is measured by odds ratio with 95 % confidence interval. A binary logistic regression analysis is made to obtain odds ratio and the confidence interval of statistical associations. The goodness of fit had tested by Hosmer-Lemeshow statistic and all variables with P-value greater than 0.05 are fitted to the multivariate model. Variables with P < 0.2 in the bivariate analysis are included in the final model, and statistical significance is declared at P < 0.05. RESULT Eighty percent (80.4 %) study participants had good knowledge on essential new born care and 92.9 % had the good practice of essential new born care. About 60 % of mothers applied butter or oil on the cord stump for their last baby. Marital status and education are significantly associated with knowledge, whereas urban residence mothers with good knowledge on essential newborn care and employed mothers are significantly associated with mothers' practice of essential newborn care. CONCLUSION Almost all mothers know and practice essential newborn care correctly except oil or butter application to the cord stump is highly practiced which should be avoided. Only marital status and educational status are significantly associated with mothers' knowledge.